3,4-di-substituted pyridine compound, methods of using and compositions comprising the same

ABSTRACT

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid is useful in the modulation of blood or serum uric acid levels. In some embodiments, 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid is used in the treatment or prevention of disorders related to aberrant levels of uric acid. In some embodiments, 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid is used for reducing serum uric acid levels in a human. Also described herein are compositions comprising 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid, and their use in the modulation of blood or serum uric acid levels.

CROSS-REFERENCE

This application is filed pursuant to 35 USC 371 as a United StatesNational Phase Application of International Application Serial No.PCT/US2012/063415, filed Nov. 2, 2012, which claims the benefit of andthe right of priority to U.S. Application Ser. No. 61/555,450, filedNov. 3, 2011, and U.S. Application Ser. No. 61/616,363, filed Mar. 27,2012, which are hereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

Uric acid is the result of the oxidation of xanthine. Disorders of uricacid metabolism include, but are not limited to, polycythemia, myeloidmetaplasia, gout, a recurrent gout attack, gouty arthritis,hyperuricaemia, hypertension, a cardiovascular disease, coronary heartdisease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidneydisease, kidney stones, kidney failure, joint inflammation, arthritis,urolithiasis, plumbism, hyperparathyroidism, psoriasis or sarcoidosis.

SUMMARY OF THE INVENTION

In certain embodiments, provided herein is a compound for use inreducing serum uric acid levels in a human, wherein the compound is2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound for use, less than 100 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, is administered to thehuman. In certain embodiments, less than 50 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, is administered to thehuman. In some embodiments, about 40 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, is administered to thehuman. In certain embodiments, about 20 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, is administered to thehuman. In some embodiments, less than 20 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, is administered to thehuman. In certain embodiments, about 5 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, is administered to thehuman. In certain embodiments, less than 5 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidis administered to the human. In some embodiments, about 2 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, is administered to thehuman. In certain embodiments, less than 2 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, is administered to thehuman. In some embodiments, about 1 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidis administered to the human.

In certain embodiments of the compound for use, 24 hours afteradministration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 0.5 mg/dL. In some embodiments, 24 hoursafter administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 0.8 mg/dL. In certain embodiments, 24hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 1 mg/dL. In some embodiments, 24 hoursafter administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidslevels are reduced by at least 2 mg/dL. In certain embodiments, 24 hoursafter administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidslevels are reduced by at least 3 mg/dL.

In some embodiments, 48 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 0.5 mg/dL. In certain embodiments, 48hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 1 mg/dL. In some embodiments, 48 hoursafter administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 3 mg/dL.

In certain embodiments, 72 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 0.5 mg/dL. In some embodiments, 72 hoursafter administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 1 mg/dL. In certain embodiments, 72 hoursafter administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by about 2 mg/dL.

In some embodiments of the compound for use, 24 hours afteradministration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,the serum uric acid levels are reduced by at least 15% from baseline. Incertain embodiments, 24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 20% from baseline. In some embodiments,24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 30% from baseline. In certainembodiments, 24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 40% from baseline. In some embodiments,24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by about 20% from baseline. In certain embodiments,24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by about 40% from baseline. In some embodiments, 24hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by about 60% from baseline.

In certain embodiments, 48 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by about 10% from baseline. In some embodiments, 48hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 20% from baseline. In certainembodiments, 48 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 30% from baseline. In some embodiments,48 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by about 40% from baseline. In certain embodiments,48 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by about 50% from baseline. In some embodiments, 72hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 15% from baseline. In certainembodiments, 72 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 20% from baseline. In some embodiments,72 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by about 20% from baseline. In certain embodiments,72 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by about 30% from baseline.

In certain embodiments, the compound is for use in treating orpreventing a condition characterized by abnormal tissue or organ levelsof uric acid. In some embodiments, the condition is gout, a recurrentgout attack, gouty arthritis, hyperuricaemia, hypertension, acardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome,Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidneyfailure, joint inflammation, arthritis, urolithiasis, plumbism,hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guaninephosphoribosyltransferase (HPRT) deficiency or a combination thereof. Inspecific embodiments, the condition is gout.

In certain embodiments of the compound for use, a second agent effectivefor the treatment of the gout is administered to the human. In someembodiments, the second agent is a URAT 1 inhibitor, a xanthine oxidaseinhibitor, a xanthine dehydrogenase, a xanthine oxidoreductaseinhibitor, or combinations thereof. In certain embodiments, the URAT 1inhibitor is2-((5-bromo-4-(4-cyclopropyl-1-naphthalenyl)-4H-1,2,4-triazol-3-yl)thio)aceticacid, or a pharmaceutically acceptable salt thereof. In someembodiments, the xanthine oxidase inhibitor is allopurinol orfebuxostat.

In certain embodiments, provided herein are methods of reducing serumuric acid levels in a human, comprising administering2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, to the human.

In some embodiments, the method comprises administering less than 100mg, less than 50 mg per day, about 40 mg per day, about 20 mg per day,less than 20 mg per day, about 5 mg per day, less than 5 mg per day,about 2 mg per day, less than 2 mg per day, or about 1 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidor a pharmaceutically acceptable salt thereof.

In some embodiments, the serum uric acid levels are reduced by at least0.5 mg/dL, at least 0.8 mg/dL, at least 1 mg/dL, at least 2 mg/dL, or atleast 3 mg/dL 24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof. In certain embodiments,the serum uric acid levels are reduced by at least 0.5 mg/dL, at least 1mg/dL, or at least 3 mg/dL 48 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof. In certain embodiments,the serum uric acid levels are reduced by at least 0.5 mg/dL, at least 1mg/dL, or 2 mg/dL 72 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof.

In some embodiments, the serum uric acid levels are reduced by at least15% from baseline, at least 20% from baseline, at least 30% frombaseline, at least 40% from baseline, about 20% from baseline, or about40% from baseline, about 60% from baseline 24 hours after administrationof 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoicacid, or a pharmaceutically acceptable salt thereof. In someembodiments, the serum uric acid levels are reduced by at about 10% frombaseline, at least 20% from baseline, at least 30% from baseline, about40% from baseline, or about 50% from baseline 48 hours afteradministration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,of a pharmaceutically acceptable salt thereof. In certain embodiments,the serum uric acid levels are reduced by at least 15% from baseline, atleast 20% from baseline, about 20% from baseline, or about 30% frombaseline 72 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof.

In some embodiments, the method is for treating or preventing acondition characterized by abnormal tissue or organ levels of uric acid.In certain embodiments, the condition is gout, a recurrent gout attack,gouty arthritis, hyperuricaemia, hypertension, a cardiovascular disease,coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmillersyndrome, kidney disease, kidney stones, kidney failure, jointinflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism,psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase(HPRT) deficiency or a combination thereof. In specific embodiments, thecondition is gout.

In certain embodiments, the methods further comprise administering asecond agent effective for the treatment of the gout. In someembodiments, the second agent is a URAT 1 inhibitor, a xanthine oxidaseinhibitor, a xanthine dehydrogenase, a xanthine oxidoreductaseinhibitor, or combinations thereof. In certain embodiments, the URAT 1inhibitor is2-((5-bromo-4-(4-cyclopropyl-1-naphthalenyl)-4H-1,2,4-triazol-3-yl)thio)aceticacid, or a pharmaceutically acceptable salt or ester thereof. In someembodiments, the xanthine oxidase inhibitor is allopurinol orfebuxostat.

In certain embodiments, provided herein is a use of a compound in themanufacture of a medicament for reducing serum uric acid levels in ahuman, wherein the compound is2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof.

In some embodiments of the use of a compound in the manufacture of amedicament, less than 100 mg per day, less than 50 mg per day, about 40mg per day, about 20 mg per day, less than 20 mg per day, about 5 mg perday, less than 5 mg per day, about 2 mg per day, less than 2 mg per day,or about 1 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidis administered to the human.

In certain embodiments of the use of a compound in the manufacture of amedicament, 24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 0.5 mg/dL, at least 0.8 mg/dL, at least 1mg/dL, at least 2 mg/dL, or at least 3 mg/dL. In some embodiments, 48hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 0.5 mg/dL, at least 1 mg/dL, or at least3 mg/dL. In certain embodiments, 72 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 0.5 mg/dL, at least 1 mg/dL, or about 2mg/dL.

In some embodiments of the use of a compound in the manufacture of amedicament, 24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,the serum uric acid levels are reduced by at least 15% from baseline, atleast 20% from baseline, at least 30% from baseline, at least 40% frombaseline, about 20% from baseline, about 40% from baseline, or about 60%from baseline. In certain embodiments, 48 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by about 10% from baseline, at least 20% frombaseline, at least 30% from baseline, about 40% from baseline, or about50% from baseline. In some embodiments, 72 hours after administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof, the serum uric acidlevels are reduced by at least 15% from baseline, at least 20% frombaseline, about 20% from baseline, or about 30% from baseline.

In certain embodiments of the use of a compound in the manufacture of amedicament, the medicament is for use in treating or preventing acondition characterized by abnormal tissue or organ levels of uric acid.In some embodiments, the condition is gout, a recurrent gout attack,gouty arthritis, hyperuricaemia, hypertension, a cardiovascular disease,coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmillersyndrome, kidney disease, kidney stones, kidney failure, jointinflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism,psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase(HPRT) deficiency or a combination thereof. In specific embodiments, thecondition is gout.

In certain embodiments of the use of a compound in the manufacture of amedicament, the medicament is administered with a second agent effectivefor the treatment of the gout. In some embodiments, the second agent isa URAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthinedehydrogenase, a xanthine oxidoreductase inhibitor, or combinationsthereof. In certain embodiments, the URAT 1 inhibitor is2-((5-bromo-4-(4-cyclopropyl-1-naphthalenyl)-4H-1,2,4-triazol-3-yl)thio)aceticacid, or a pharmaceutically acceptable salt or ester thereof. In someembodiments, the xanthine oxidase inhibitor is allopurinol orfebuxostat.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1A shows a schematic representation of schedule of events duringthe trial described in Example 3.

FIG. 1B shows a schematic representation of schedule of events duringthe trial described in Example 5.

FIG. 2A shows the absolute serum uric acid concentrations (mg/dL)measured 0-72 hours post-dose for Group 1 (2 mg, fasted). Subjects 1 and2 received placebo; subjects 3-8 received active.

FIG. 2B shows the % serum uric acid change from baseline measured 0-72hours post-dose for Group 1 (2 mg, fasted). Subjects 1 and 2 receivedplacebo; subjects 3-8 received active.

FIG. 3A shows the absolute serum uric acid concentrations (mg/dL)measured 0-72 hours post-dose for Group 2 (5 mg, fasted). Subjects 1 and2 received placebo; subjects 3-8 received active.

FIG. 3B shows the % serum uric acid change from baseline measured 0-72hours post-dose for Groups 2 and 3 (5 mg, fasted and fed respectively).Subjects 1 and 2 received placebo; subjects 3-8 received active.

FIG. 4A shows the absolute serum uric acid concentrations (mg/dL)measured 0-72 hours post-dose for Groups 4 and 5 (20 mg, fasted and fedrespectively). Subjects 1 and 2 received placebo; subjects 3-8 receivedactive.

FIG. 4B shows the % serum uric acid change from baseline measured 0-72hours post-dose for Groups 4 and 5 (20 mg, fasted and fed respectively).Subjects 1 and 2 received placebo; subjects 3-8 received active.

FIG. 5A shows the absolute serum uric acid concentrations (mg/dL)measured 0-72 hours post-dose for Group 6 (40 mg, fasted). Subjects 1and 2 received placebo; subjects 3-8 received active.

FIG. 5B shows the % serum uric acid change from baseline measured 0-72hours post-dose for Group 6 (40 mg, fasted). Subjects 1 and 2 receivedplacebo; subjects 3-8 received active.

FIG. 6A shows the absolute serum uric acid concentrations (mg/dL)measured 0-72 hours post-dose for Groups 1, 2, 4 and 6 (2 mg, 5 mg, 20mg and 40 mg respectively, all fasted).

FIG. 6B shows the % serum uric acid change from baseline measured 0-72hours post-dose for Groups 1, 2, 4 and 6 (2 mg, 5 mg, 20 mg and 40 mgrespectively, all fasted).

FIG. 7A shows the absolute serum uric acid concentrations (mg/dL; meanplacebo-subjects 1, 2 and 3; and mean active-subjects 4-12), measured atnominal timepoints (days 0-9—once daily dosing, plus days 10-13, postdosing) for twelve subjects in group 7 (1 mg, once daily for 10 days),as described in example 6A.

FIG. 7B shows the % serum uric acid change from baseline (meanplacebo-subjects 1, 2 and 3; and mean active-subjects 4-12), measured atnominal timepoints (days 0-9—once daily dosing, plus days 10-13, postdosing) for twelve subjects in group 7 (1 mg, once daily for 10 days),as described in example 6A.

FIG. 8A shows the absolute serum uric acid concentrations (mg/dL; meanplacebo-subjects 1, 2 and 3; and mean active-subjects 4-10), measured atnominal timepoints (days 0-9—once daily dosing, plus days 10-13, postdosing) for ten subjects in group 8 (5 mg, once daily for 10 days), asdescribed in example 6B.

FIG. 8B shows the % serum uric acid change from baseline (meanplacebo-subjects 1, 2 and 3; and mean active-subjects 4-10), measured atnominal timepoints (days 0-9—once daily dosing, plus days 10-13, postdosing) for ten subjects in group 8 (1 mg, once daily for 10 days), asdescribed in example 6B.

FIG. 9A shows the absolute serum uric acid concentrations (mg/dL; meanplacebo-subjects 1, 2 and 3; and mean active-subjects 4-11), measured atnominal timepoints (days 0-9—once daily dosing, plus days 10-13, postdosing) for eleven subjects in group 9 (10 mg, once daily for 10 days),as described in example 6C.

FIG. 9B shows the % serum uric acid change from baseline (meanplacebo-subjects 1, 2 and 3; and mean active-subjects 4-11), measured atnominal timepoints (days 0-9—once daily dosing, plus days 10-13, postdosing) for eleven subjects in group 9 (10 mg, once daily for 10 days),as described in example 6C.

FIG. 10A shows the mean absolute serum uric acid concentrations (mg/dL),measured at nominal timepoints (days 0-9—once daily dosing, plus days10-13, post dosing) for groups 7, 8 and 9 (1 mg, 5 mg and 10 mgrespectively, once daily for 10 days, placebo groups pooled), asdescribed in example 6.

FIG. 10B shows the mean % serum uric acid change from baseline measuredat nominal timepoints (days 0-9—once daily dosing, plus days 10-13, postdosing) for groups 7, 8 and 9 (1 mg, 5 mg and 10 mg respectively, oncedaily for 10 days, placebo groups pooled), as described in example 6.

DETAILED DESCRIPTION OF THE INVENTION

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Certain Pharmaceutical Terminology

The term “patient”, “subject” or “individual” are used interchangeably.As used herein, they refer to individuals suffering from a disorder, andthe like, encompasses mammals and non-mammals. None of the terms requirethat the individual be under the care and/or supervision of a medicalprofessional. Mammals are any member of the Mammalian class, includingbut not limited to humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In some embodiments of the methods andcompositions provided herein, the individual is a mammal. In preferredembodiments, the individual is a human.

The terms “treat,” “treating” or “treatment,” and other grammaticalequivalents as used herein, include alleviating, abating or amelioratinga disease or condition or one or more symptoms thereof, preventingadditional symptoms, ameliorating or preventing the underlying metaboliccauses of symptoms, inhibiting the disease or condition, e.g., arrestingthe development of the disease or condition, relieving the disease orcondition, causing regression of the disease or condition, relieving acondition caused by the disease or condition, or stopping the symptomsof the disease or condition, and are intended to include prophylaxis.The terms further include achieving a therapeutic benefit and/or aprophylactic benefit. By therapeutic benefit is meant eradication oramelioration of the underlying disorder being treated. Also, atherapeutic benefit is achieved with the eradication or amelioration ofone or more of the physiological symptoms associated with the underlyingdisorder such that an improvement is observed in the individual,notwithstanding that the individual is still be afflicted with theunderlying disorder. For prophylactic benefit, the compositions areadministered to an individual at risk of developing a particulardisease, or to an individual reporting one or more of the physiologicalsymptoms of a disease, even though a diagnosis of this disease has notbeen made.

The term “about” generally refers to a range of numbers that one ofskill in the art would consider equivalent to the recited value (e.g.,having the same function or result). In many instances, the term “about”may include numbers that are rounded to the nearest significant figure.In preferred instances, the term “about” means within 10% of a givenvalue or range.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein. In preferred embodiments, the compounds andcompositions described herein are administered orally.

The terms “effective amount”, “therapeutically effective amount” or“pharmaceutically effective amount” as used herein, refer to asufficient amount of at least one agent or compound being administeredwhich will relieve to some extent one or more of the symptoms of thedisease or condition being treated. The result can be reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic uses is the amount of the composition comprising2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidrequired to provide a clinically significant decrease in a disease. Anappropriate “effective” amount may differ from one individual toanother. An appropriate “effective” amount in any individual case may bedetermined using techniques, such as a dose escalation study.

The term “acceptable” as used herein, with respect to a formulation,composition or ingredient, means having no persistent detrimental effecton the general health of the individual being treated.

The term “pharmaceutically acceptable” as used herein, refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,and is relatively nontoxic, i.e., the material may be administered to anindividual without causing undesirable biological effects or interactingin a deleterious manner with any of the components of the composition inwhich it is contained.

The term “prodrug” as used herein, refers to a drug precursor that,following administration to an individual and subsequent absorption, isconverted to an active, or a more active species via some process, suchas conversion by a metabolic pathway. Thus, the term encompasses anyderivative of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,which, upon administration to a recipient, is capable of providing,either directly or indirectly,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidor a pharmaceutically active metabolite or residue thereof. Someprodrugs have a chemical group present on the prodrug that renders itless active and/or confers solubility or some other property to thedrug. Once the chemical group has been cleaved and/or modified from theprodrug the active drug is generated. Prodrugs are often useful because,in some situations, they may be easier to administer than the parentdrug. They may, for instance, be bioavailable by oral administrationwhereas the parent is not. Particularly favored derivatives or prodrugsare those that increase the bioavailability of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwhen administered to an individual (e.g. by allowing an orallyadministered compound to be more readily absorbed into the blood) orwhich enhance delivery of the parent compound to a biologicalcompartment (e.g. the brain or lymphatic system).

The term “pharmaceutically acceptable salt” as used herein, refers tosalts that retain the biological effectiveness of the free acids andbases of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidand that are not biologically or otherwise undesirable.2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidmay react with inorganic or organic bases, and inorganic and organicacids, to form a pharmaceutically acceptable salt. These salts can beprepared in situ during the final isolation and purification, or byseparately reacting the purified compound in its free base form with asuitable organic or inorganic acid, and isolating the salt thus formed.

The term “pharmaceutical composition,” as used herein, refers to abiologically active compound, optionally mixed with at least onepharmaceutically acceptable chemical component, such as, though notlimited to carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, excipients and the like.

The term “carrier” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The terms “pharmaceutical combination”, “administering an additionaltherapy”, “administering an additional therapeutic agent” and the like,as used herein, refer to a pharmaceutical therapy resulting from themixing or combining of more than one active ingredient and includes bothfixed and non-fixed combinations of the active ingredients. The term“fixed combination” means that2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,and at least one co-agent, are both administered to an individualsimultaneously in the form of a single entity or dosage. The term“non-fixed combination” means that2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,and at least one co-agent, are administered to an individual as separateentities either simultaneously, concurrently or sequentially withvariable intervening time limits, wherein such administration provideseffective levels of the two or more compounds in the body of theindividual. These also apply to cocktail therapies, e.g. theadministration of three or more active ingredients.

The terms “co-administration”, “administered in combination with” andtheir grammatical equivalents or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singleindividual, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different times. In some embodiments2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwill be co-administered with other agents. These terms encompassadministration of two or more agents to an animal so that both agentsand/or their metabolites are present in the animal at the same time.They include simultaneous administration in separate compositions,administration at different times in separate compositions, and/oradministration in a composition in which both agents are present. Thus,in some embodiments,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidand the other agent(s) are administered in a single composition. In someembodiments,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidand the other agent(s) are admixed in the composition.

The term “metabolite,” as used herein, refers to a derivative of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidformed when the compound is metabolized.

The term “active metabolite,” as used herein, refers to a biologicallyactive derivative of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidformed when the compound is metabolized.

The term “metabolized,” as used herein, refers to the sum of theprocesses (including, but not limited to, hydrolysis reactions andreactions catalyzed by enzymes) by which a particular substance ischanged by an organism. Thus, enzymes may produce specific structuralalterations to a compound. For example, cytochrome P450 catalyzes avariety of oxidative and reductive reactions while uridine diphosphateglucuronyltransferases catalyze the transfer of an activatedglucuronic-acid molecule to aromatic alcohols, aliphatic alcohols,carboxylic acids, amines and free sulfhydryl groups. Further informationon metabolism may be obtained from The Pharmacological Basis ofTherapeutics, 9th Edition, McGraw-Hill (1996).

Modes of Administration

In some embodiments,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidis administered either alone or in combination with pharmaceuticallyacceptable carriers, excipients or diluents, in a pharmaceuticalcomposition. Administration can be effected by any method that enablesdelivery of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidto the site of action. These methods include, though are not limited todelivery via enteral routes (including oral, gastric or duodenal feedingtube, rectal suppository and rectal enema), parenteral routes (injectionor infusion, including intraarterial, intracardiac, intradermal,intraduodenal, intramedullary, intramuscular, intraosseous,intraperitoneal, intrathecal, intravascular, intravenous, intravitreal,epidural and subcutaneous), inhalational, transdermal, transmucosal,sublingual, buccal and topical (including epicutaneous, dermal, enema,eye drops, ear drops, intranasal, vaginal) administration, although themost suitable route may depend upon for example the condition anddisorder of the recipient. By way of example only,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidcan be administered locally to the area in need of treatment, by forexample, local infusion during surgery, topical application such ascreams or ointments, injection, catheter, or implant, said implant madefor example, out of a porous, non-porous, or gelatinous material,including membranes, such as silastic membranes, or fibers. Theadministration can also be by direct injection at the site of a diseasedtissue or organ.

In some embodiments, formulations suitable for oral administration arepresented as discrete units such as capsules, cachets or tablets eachcontaining a predetermined amount of the active ingredient; as a powderor granules; as a solution or a suspension in an aqueous liquid or anon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. In some embodiments, the active ingredientis presented as a bolus, electuary or paste.

Pharmaceutical preparations that can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. In some embodiments, the tabletsare coated or scored and are formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In some embodiments, stabilizers are added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or Dragee coatings for identification or to characterizedifferent combinations of active compound doses.

In some embodiments, pharmaceutical preparations are formulated forparenteral administration by injection, e.g., by bolus injection orcontinuous infusion. Formulations for injection may be presented in unitdosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored inpowder form or in a freeze-dried (lyophilized) condition requiring onlythe addition of the sterile liquid carrier, for example, saline orsterile pyrogen-free water, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets of the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidto allow for the preparation of highly concentrated solutions.

Pharmaceutical preparations may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidmay be formulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

Pharmaceutical preparations may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter, polyethyleneglycol, or other glycerides.

Pharmaceutical preparations may be administered topically, that is bynon-systemic administration. This includes the application of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidexternally to the epidermis or the buccal cavity and the instillationinto the ear, eye and nose, such that the compound does notsignificantly enter the blood stream. In contrast, systemicadministration refers to oral, intravenous, intraperitoneal andintramuscular administration.

Pharmaceutical preparations suitable for topical administration includeliquid or semi-liquid preparations suitable for penetration through theskin to the site of inflammation such as gels, liniments, lotions,creams, ointments or pastes, and drops suitable for administration tothe eye, ear or nose. The active ingredient may comprise, for topicaladministration, from 0.001% to 10% w/w, for instance from 1% to 2% byweight of the formulation. It may however comprise as much as 10% w/wbut preferably will comprise less than 5% w/w, more preferably from 0.1%to 1% w/w of the formulation.

Pharmaceutical preparations for administration by inhalation areconveniently delivered from an insufflator, nebulizer pressurized packsor other convenient means of delivering an aerosol spray. Pressurizedpacks may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, pharmaceuticalpreparations may take the form of a dry powder composition, for examplea powder mix with a suitable powder base such as lactose or starch. Thepowder composition may be presented in unit dosage form, in for example,capsules, cartridges, gelatin or blister packs from which the powder maybe administered with the aid of an inhalator or insufflator.

It should be understood that in addition to the ingredients particularlymentioned above,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidmay include other agents conventional in the art having regard to thetype of formulation in question, for example those suitable for oraladministration may include flavoring agents.

Formulations

2-((3-(4-Cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidcan be delivered in a vesicle, such as a liposome.2-((3-(4-Cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidcan also be delivered in a controlled release system, or a controlledrelease system can be placed in proximity of the therapeutic target. Inone embodiment, a pump may be used.

The pharmaceutical compositions described herein can also contain theactive ingredient in a form suitable for oral use, for example, astablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use are optionally preparedaccording to known method, and such compositions may contain one or moreagents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,such as microcrystalline cellulose, sodium croscarmellose, corn starch,or alginic acid; binding agents, for example starch, gelatin,polyvinyl-pyrrolidone or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be un-coatedor coated by known techniques to mask the taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropylmethyl-cellulose orhydroxypropylcellulose, or a time delay material such as ethylcellulose, or cellulose acetate butyrate may be employed as appropriate.Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefore,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidmay be combined with various sweetening or flavoring agents, coloringmatters or dyes and, if desired, emulsifying agents or suspendingagents, together with diluents such as water, ethanol, propylene glycol,glycerin, or combinations thereof.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

Pharmaceutical compositions may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil, for example olive oilor arachis oil, or a mineral oil, for example liquid paraffin ormixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening agents, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

Pharmaceutical compositions may be in the form of a sterile injectableaqueous solution. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. The sterile injectable preparation may also be a sterileinjectable oil-in-water microemulsion where the active ingredient isdissolved in the oily phase. For example, the active ingredient may befirst dissolved in a mixture of soybean oil and lecithin. The oilsolution then introduced into a water and glycerol mixture and processedto form a microemulsion. The injectable solutions or microemulsions maybe introduced into an individual's blood-stream by local bolusinjection. Alternatively, it may be advantageous to administer thesolution or microemulsion in such a way as to maintain a constantcirculating concentration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid.In order to maintain such a constant concentration, a continuousintravenous delivery device may be utilized. An example of such a deviceis the Deltec CADD-PLUS™ model 5400 intravenous pump. The pharmaceuticalcompositions may be in the form of a sterile injectable aqueous oroleagenous suspension for intramuscular and subcutaneous administration.This suspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butane diol. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose any blandfixed oil may be employed including synthetic mono- or diglycerides. Inaddition, fatty acids such as oleic acid find use in the preparation ofinjectables.

Pharmaceutical compositions may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the active ingredient with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter, glycerinatedgelatin, hydrogenated vegetable oils, mixtures of polyethylene glycolsof various molecular weights and fatty acid esters of polyethyleneglycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidcan be used. As used herein, topical application can include mouthwashes and gargles.

Pharmaceutical compositions may be administered in intranasal form viatopical use of suitable intranasal vehicles and delivery devices, or viatransdermal routes, using transdermal skin patches. To be administeredin the form of a transdermal delivery system, the dosage administrationwill, of course, be continuous rather than intermittent throughout thedosage regimen.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing into association2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidor a pharmaceutically acceptable salt, ester, prodrug or solvate thereof(“active ingredient”) with the carrier which constitutes one or moreaccessory ingredients. In general, the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both and then,if necessary, shaping the product into the desired formulation.

Dosage Forms

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionmay include a conventional pharmaceutical carrier or excipient and2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidas an active ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidin sterile aqueous solutions, for example, aqueous propylene glycol ordextrose solutions. Such dosage forms can be suitably buffered, ifdesired.

Doses

The amount of pharmaceutical composition administered will firstly bedependent on the mammal being treated. In the instances wherepharmaceutical compositions are administered to a human individual, thedaily dosage will normally be determined by the prescribing physicianwith the dosage generally varying according to the age, sex, diet,weight, general health and response of the individual, the severity ofthe individual's symptoms, the precise indication or condition beingtreated, the severity of the indication or condition being treated, timeof administration, route of administration, the disposition of thecomposition, rate of excretion, drug combination, and the discretion ofthe prescribing physician. Also, the route of administration may varydepending on the condition and its severity. Preferably, thepharmaceutical composition is in unit dosage form. In such form, thepreparation is subdivided into unit doses containing appropriatequantities of the active component, e.g., an effective amount to achievethe desired purpose. Determination of the proper dosage for a particularsituation is within the skill of the art. In some instances, treatmentmay be initiated with smaller dosages which are less than the optimumdose of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid.Thereafter, the dosage is increased by small amounts until the optimumeffect under the circumstances is reached. For convenience, the totaldaily dosage may be divided and administered in portions during the dayif desired. The amount and frequency of administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,and if applicable other therapeutic agents and/or therapies, will beregulated according to the judgment of the attending clinician(physician) considering such factors as described above. Thus the amountof pharmaceutical composition to be administered may vary widely.

Administration may occur in an amount of less than about 50 mg/kg ofbody weight per day (administered in single or divided doses). Aparticular therapeutic dosage can include, e.g., less than about 1000 mgof 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoicacid, and preferably includes, e.g., less than about 250 mg. Thequantity of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidin a unit dose of preparation may be varied or adjusted from less thanabout 500 mg, preferably from less than about 100 mg, more preferablyfrom less than about 50 mg, or from less than 5 mg, according to theparticular application. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, e.g. by dividing such larger doses into several small dosesfor administration throughout the day. In combinational applications inwhich 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoicacid is not the sole therapy, it may be possible to administer lesseramounts and still have therapeutic or prophylactic effect.

In some embodiments,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidis administered once a day. In other embodiments,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidis administered twice a day. In some embodiments,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidis administered with food. In other embodiments,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidis administered without food.

The therapeutic dosing of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic aciddescribed in the section entitled “Methods of Reducing Serum Uric AcidLevels” and the examples may be used to treat any of the diseasesdescribed herein.

Combination Therapies

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidor a pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof may be administered as a sole therapy, or incombination with another therapy or therapies.

For example, therapeutic effectiveness may be enhanced by administrationof an adjuvant (i.e., by itself the adjuvant may only have minimaltherapeutic benefit, but in combination with another therapeutic agent,the overall therapeutic benefit to the individual is enhanced). Or, byway of example only, the benefit experienced by an individual may beincreased by administering2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwith another therapeutic agent (which also includes a therapeuticregimen) that also has therapeutic benefit. By way of example only, in atreatment for gout, increased therapeutic benefit may result by alsoproviding the individual with another therapeutic agent for gout. Or,the additional therapy or therapies may include, but are not limited tophysiotherapy, psychotherapy, radiation therapy, application ofcompresses to a diseased area, rest, altered diet, and the like.Regardless of the disease, disorder or condition being treated, theoverall benefit experienced by the individual may be additive of the twotherapies or therapeutic agents or the individual may experience asynergistic benefit.

In the instances where2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidis administered in combination with other therapeutic agents,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidneed not be administered in the same pharmaceutical composition as othertherapeutic agents, and may, because of different physical and chemicalcharacteristics, be administered by a different route. For example,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidmay be administered orally to generate and maintain good blood levelsthereof, while the other therapeutic agent may be administeredintravenously. Thus2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidmay be administered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol), sequentially ordosed separately to other therapeutic agents. The initial administrationcan be made according to established protocols known in the art, andthen, based upon the observed effects, the dosage, modes ofadministration and times of administration can be modified by theskilled clinician.

The particular choice of other therapeutic agent will depend upon thediagnosis of the attending physicians and their judgment of thecondition of the individual and the appropriate treatment protocol. Insome embodiments, the additional agent is a URAT 1 inhibitor, a xanthineoxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductaseinhibitor, a purine nucleoside phosphorylase (PNP) inhibitor, a uricacid transporter inhibitor, a glucose transporter (GLUT) inhibitor, aGLUT-9 inhibitor, a solute carrier family 2 (facilitated glucosetransporter), member 9 (SLC2A9) inhibitor, an organic anion transporter(OAT) inhibitor, an OAT-4 inhibitor, or combinations thereof. In certaininstances, URAT 1 is an ion exchanger that mediates uratetransportation. In certain instances, URAT I mediates uratetransportation in the proximal tubule. In certain instances, URAT Iexchanges urate in a proximal tubule for lactate and nicotinate. Incertain instances, xanthine oxidase oxidizes hypoxanthine to xanthine,and further to uric acid. In certain instances, xanthine dehydrogenasecatalyzes the conversion of xanthine, NAD⁺, and H₂O into urate, NADH,and H⁺. In some embodiments, the additional agent is2-((5-bromo-4-(4-cyclopropyl-1-naphthalenyl)-4H-1,2,4-triazol-3-yl)thio)aceticacid, allopurinol, febuxostat(2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid),FYX-051(4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile),probenecid, sulfinpyrazone, benzbromarone, acetaminophen, steroids,nonsteroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropichormone (ACTH), colchicine, a glucorticoid, an adrogen, a cox-2inhibitor, a PPAR agonist, naproxen, sevelamer, sibutmaine,troglitazone, proglitazone, another uric acid lowering agent, losartan,fibric acid, benziodarone, salicylate, anlodipine, vitamin C, orcombinations thereof.

Diseases

Described herein are methods of treating a disease in an individualsuffering from said disease comprising administering to said individualan effective amount of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidor a pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof.

Also described herein are methods of preventing or delaying onset of adisease in an individual at risk for developing said disease comprisingadministering to said individual an effective amount to prevent or delayonset of said disease, of a composition comprising2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidor a pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof.

Further described herein are methods for the prophylaxis or treatment ofany disease or disorder in which aberrant levels of uric acid plays arole including, without limitation: hyperuricemia, gout, goutyarthritis, inflammatory arthritis, kidney disease, nephrolithiasis(kidney stones), joint inflammation, deposition of urate crystals injoints, urolithiasis (formation of calculus in the urinary tract),deposition of urate crystals in renal parenchyma, Lesch-Nyhan syndrome,Kelley-Seegmiller syndrome, gout flare, tophaceous gout, kidney failure,or combinations thereof in a human or other mammal. The methodsdisclosed herein extend to such a use and to the use of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidfor the manufacture of a medicament for treating such diseases ordisorders. Further, the methods disclosed herein extend to theadministration to a human an effective amount of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidfor treating any such disease or disorder.

Individuals that can be treated with2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof, according to the methods of this inventioninclude, for example, individuals that have been diagnosed as havinggout, gouty arthritis, inflammatory arthritis, kidney disease,nephrolithiasis (kidney stones), joint inflammation, deposition of uratecrystals in joints, urolithiasis (formation of calculus in the urinarytract), deposition of urate crystals in renal parenchyma, Lesch-Nyhansyndrome, Kelley-Seegmiller syndrome, gout flare, tophaceous gout,kidney failure, or combinations thereof.

In some embodiments, an individual having an aberrant uric acid level isadministered an amount of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidsufficient to modulate the aberrant uric acid level (e.g., to amedically-acceptable level). In some embodiments, an individual treatedwith t2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoicacid displays aberrant uric acid levels wherein the uric acid levels inblood exceed a medically-accepted range (i.e., hyperuricemia). In someembodiments, an individual treated with2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic aciddisplays aberrant uric acid levels wherein uric acid levels in the bloodexceed 360 μmmol/L (6 mg/dL) for a female individual or 400 μmmol/L (6.8mg/dL) for a male individual. In some embodiments, an individual treatedwith 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoicacid displays aberrant uric acid levels wherein uric acid levels inurine exceed a medically-accepted range (i.e., hyperuricosuria). In someembodiments, an individual treated with2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic aciddisplays aberrant uric acid levels wherein uric acid levels in urineexceed 800 mg/day (in a male individual) and greater than 750 mg/day (ina female individual).

In some embodiments, an individual treated with2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid(1) displays aberrant uric acid levels, and (2) suffers from acardiovascular disorder. In some embodiments, an individual treated with2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid(1) displays aberrant uric acid levels, and (2) suffers from ananeurysm; angina; atherosclerosis; a stroke; cerebrovascular disease;congestive heart failure; coronary artery disease; and/or a myocardialinfarction. In some embodiments, an individual treated with2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid(1) displays aberrant uric acid levels, and (2) displays (a) c-reactiveprotein (CRP) levels above about 3.0 mg/L; (b) homocysteine levels aboveabout 15.9 mmol/L; (c) LDL levels above about 160 mg/dL; (d) HDL levelsbelow about 40 mg/dL; and/or (e) serum creatinine levels above about 1.5mg/dL.

In some embodiments, an individual treated with2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid(1) displays aberrant uric acid levels, and (2) suffers from diabetes.In some embodiments, an individual treated with2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoic acid(1) displays aberrant uric acid levels, and (2) suffers from Type Idiabetes. In some embodiments, an individual treated with2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoic acid(1) displays aberrant uric acid levels, and (2) suffers from Type IIdiabetes. In some embodiments, an individual treated with2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoic acid(1) displays aberrant uric acid levels, and (2) suffers from a loss ofbeta cells of the islets of Langerhans in the pancreas. In someembodiments, an individual treated with 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid (1) displays aberrant uricacid levels, and (2) suffers from insulin resistance and/or reducedinsulin sensitivity. In some embodiments, an individual treated with2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoic acid(1) displays aberrant uric acid levels, and (2) displays (a) a fastingplasma glucose level ≥126 mg/dL; (b) a plasma glucose level ≥200 mg/dLtwo hours after a glucose tolerance test; and/or (c) symptoms ofhyperglycemia and casual plasma glucose levels ≥200 mg/dL (11.1 mmol/l).

In some embodiments, an individual treated with2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoic acid(1) displays aberrant uric acid levels, and (2) suffers from metabolicsyndrome. In some embodiments, an individual treated with2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoic acid(1) displays aberrant uric acid levels, and (2) suffers from (a)diabetes mellitus, impaired glucose tolerance, impaired fasting glucoseand/or insulin resistance, (b) at least two of (i) blood pressure:≥140/90 mmHg; (ii) dyslipidaemia: triglycerides (TG): ≥1.695 mmol/L andhigh-density lipoprotein cholesterol (HDL-C)≤0.9 mmol/L (male), ≤1.0mmol/L (female); (iii) central obesity:waist:hip ratio >0.90(male); >0.85 (female), and/or body mass index >30 kg/m2; and (iv)microalbuminuria: urinary albumin excretion ratio≥20 mg/min oralbumin:creatinine ratio≥30 mg/g. In some embodiments, an individualtreated with 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid (1) displays aberrant uric acid levels, and(2) suffers from insulin resistance (i.e., the top 25% of the fastinginsulin values among non-diabetic individuals) and (b) at least two of(i) central obesity: waist circumference ≥94 cm (male), ≥80 cm (female);(ii) dyslipidaemia: TG≥2.0 mmol/L and/or HDL-C<1.0 mmol/L or treated fordyslipidaemia; (iii) hypertension: blood pressure ≥140/90 mmHg orantihypertensive medication; and (iv) fasting plasma glucose ≥6.1mmol/L. In some embodiments, an individual treated with2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoic acid(1) displays aberrant uric acid levels, and (2) displays at least threeof (a) elevated waist circumference: Men ≥40 inches (men) and ≥35 inches(women); (b) elevated triglycerides: ≥150 mg/dL; (c) reduced HDL: <40mg/dL (men) and <50 mg/dL (women); (d) elevated blood pressure: ≥130/85mm Hg or use of medication for hypertension; and (e) elevated fastingglucose: ≥100 mg/dL (5.6 mmol/L) or use of medication for hyperglycemia.

In some embodiments, an individual treated with2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoic acid(1) displays aberrant uric acid levels, and (2) suffers from kidneydisease or kidney failure. In some embodiments, an individual treatedwith 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid (1) displays aberrant uric acid levels, and (2) displays oliguria(decreased urine production. In some embodiments, an individual treatedwith 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid (1) displays aberrant uric acid levels, and (2) produces less than400 mL per day of urine (adults), produces less than 0.5 mL/kg/h ofurine (children), or produces less than 1 mL/kg/h of urine (infants).

Uric Acid

In certain instances, purines (adenine, guanine), derived from food ortissue turnover (cellular nucleotides undergo continuous turnover), arecatabolized in humans to their final oxidation product, uric acid. Incertain instances, guanine is oxidized to xanthine, which is turn isfurther oxidized to uric acid by the action of xanthine oxidase;adenosine is converted to inosine which is further oxidized tohypoxanthine. In certain instances, xanthine oxidase oxidizeshypoxanthine to xanthine, and further to uric acid. In certaininstances, as part of the reverse process, the enzymehypoxanthine-guanine phosphoribosyltransferase (HGPRT) salvages guanineand hypoxanthine.

In certain instances, the keto form of uric acid is in equilibrium withthe enol form which loses a proton at physiological pH to form urate. Incertain instances, (e.g., under serum conditions (pH 7.40, 37° C.)),about 98% of uric acid is ionized as the monosodium urate salt. Incertain instances, urate is a strong reducing agent and potentantioxidant. In humans, about half the antioxidant capacity of plasmacomes from uric acid.

In certain instances, most uric acid dissolves in blood and passes tothe kidneys, where it is excreted by glomerular filtration and tubularsecretion. In certain instances, a substantial fraction of uric acid isreabsorbed by the renal tubules. One of the peculiar characteristics ofthe uric acid transport system is that, although the net activity oftubular function is reabsorption of uric acid, the molecule is bothsecreted and reabsorbed during its passage through the nephron. Incertain instances, reabsorption dominates in the S1 and S3 segments ofthe proximal tubule and secretion dominates in the S2 segment. Incertain instances, the bidirectional transport results in drugs thatinhibit uric acid transport decreasing, rather than increasing, theexcretion of uric acid, compromising their therapeutic usefulness. Incertain instances, normal uric acid levels in human adults (5.1+/−0.93mg/dL) are close to the limits of urate solubility (˜7 mg/dL at 37° C.),which creates a delicate physiologic urate balance. In certaininstances, the normal uric acid range for females is approximately 1mg/dL below the male range.

Hyperuricemia

In certain instances, hyperuricemia is characterized by higher thannormal blood levels of uric acid, sustained over long periods of time.In certain instances, increased blood urate levels may be due toenhanced uric acid production (˜10-20%) and/or reduced renal excretion(˜80-90%) of uric acid. In certain instances, causes of hyperuricemiamay include:

Obesity/weight gain

Excessive alcohol use

Excessive dietary purine intake (foods such as shellfish, fish roe,scallops, peas lentils, beans and red meat, particularly offal—brains,kidneys, tripe, liver)

Certain medications, including low-dose aspirin, diuretics, niacin,cyclosporine, pyrazinamide, ethambutol, some high blood pressure drugsand some cancer chemotherapeutics, immunosuppressive and cytotoxicagents

Specific disease states, particularly those associated with a high cellturnover rate (such as malignancy, leukemia, lymphoma or psoriasis), andalso including high blood pressure, hemoglobin disorders, hemolyticanemia, sickle cell anemia, various nephropathies, myeloproliferativeand lymphoproliferative disorders, hyperparathyroidism, renal disease,conditions associated with insulin resistance and diabetes mellitus, andin transplant recipients, and possibly heart disease

Inherited enzyme defects

Abnormal kidney function (e.g. increased ATP turn over, reducedglomerular urate filtration)

Exposure to lead (plumbism or “saturnine gout”)

In certain instances, hyperuricemia may be asymptomatic, though isassociated with the following conditions:

Gout

Gouty arthritis

Uric acid stones in the urinary tract (urolithiasis)

Deposits of uric acid in the soft tissue (tophi)

Deposits of uric acid in the kidneys (uric acid nephropathy)

Impaired kidney function, possibly leading to chronic and acute renalfailure

Gout

Prevalence

The incidence of gout has increased over the past two decades and, inthe United States, affects as much as 2.7% of the population aged 20years and older, totaling over 5.1 million American adults. Gout is morecommon in men than women, (3.8% or 3.4 million men vs. 1.6% or 1.7million women), typically affecting men in their 40's and 50's (althoughgout attacks can occur after puberty which sees an increase in uric acidlevels). An increase in prevalence of gout from 2.9 to 5.2 per 1000 inthe time period 1990 to 1999 was observed, with most of the increaseoccurring in those over the age of 65. Gout attacks are more common inwomen after menopause. In certain instances, gout is one of the mostcommon forms of arthritis, accounting for approximately 5% of allarthritis cases. In certain instances, kidney failure and urolithiasisoccur in 10-18% of individuals with gout and are common sources ofmorbidity and mortality from the disease.

Leading Causes

In most cases, gout is associated with hyperuricemia. In certaininstances, individuals suffering from gout excrete approximately 40%less uric acid than nongouty individuals for any given plasma urateconcentrations. In certain instances, urate levels increase until thesaturation point is reached. In certain instances, precipitation ofurate crystals occurs when the saturation point is reached. In certaininstances, these hardened, crystallized deposits (tophi) form in thejoints and skin, causing joint inflammation (arthritis). In certaininstances, deposits are be made in the joint fluid (synovial fluid)and/or joint lining (synovial lining). Common areas for these depositsare the large toe, feet, ankles and hands (less common areas include theears and eyes). In certain instances, the skin around an affected jointbecomes red and shiny with the affected area being tender and painful totouch. In certain instances, gout attacks increase in frequency. Incertain instances, untreated acute gout attacks lead to permanent jointdamage and disability. In certain instances, tissue deposition of urateleads to: acute inflammatory arthritis, chronic arthritis, deposition ofurate crystals in renal parenchyma and urolithiasis. In certaininstances, the incidence of gouty arthritis increases 5 fold inindividuals with serum urate levels of 7 to 8.9 mg/dL and up to 50 foldin individuals with levels >9 mg/dL (530 μmol/L). In certain instances,individuals with gout develop renal insufficiency and end stage renaldisease (i.e., “gouty nephropathy”). In certain instances, goutynephropathy is characterized by a chronic interstitial nephropathy,which is promoted by medullary deposition of monosodium urate.

In certain instances, gout includes painful attacks of acute,monarticular, inflammatory arthritis, deposition of urate crystals injoints, deposition of urate crystals in renal parenchyma, urolithiasis(formation of calculus in the urinary tract), and nephrolithiasis(formation of kidney stones). In certain instances, secondary goutoccurs in individuals with cancer, particularly leukemia, and those withother blood disorders (e.g. polycythemia, myeloid metaplasia, etc).

Symptoms

In certain instances, attacks of gout develop very quickly, frequentlythe first attack occurring at night. In certain instances, symptomsinclude sudden, severe joint pain and extreme tenderness in the jointarea, joint swelling and shiny red or purple skin around the joint. Incertain instances, the attacks are infrequent lasting 5-10 days, with nosymptoms between episodes. In certain instances, attacks become morefrequent and may last longer, especially if the disorder is notcontrolled. In certain instances, episodes damage the affected joint(s)resulting in stiffness, swelling, limited motion and/or persistent mildto moderate pain.

Treatment

In certain instances, gout is treated by lowering the production of uricacid. In certain instances, gout is treated by increasing the excretionof uric acid. In certain instances, gout is treated by URAT 1, xanthineoxidase, xanthine dehydrogenase, xanthine oxidoreductase, a purinenucleoside phosphorylase (PNP) inhibitor, a uric acid transporter (URAT)inhibitor, a glucose transporter (GLUT) inhibitor, a GLUT-9 inhibitor, asolute carrier family 2 (facilitated glucose transporter), member 9(SLC2A9) inhibitor, an organic anion transporter (OAT) inhibitor, anOAT-4 inhibitor, or combinations thereof. In general, the goals of gouttreatment are to i) reduce the pain, swelling and duration of an acuteattack, and ii) prevent future attacks and joint damage. In certaininstances, gout attacks are treated successfully using a combination oftreatments. In certain instances, gout is one of the most treatableforms of arthritis.

i) Treating the Gout Attack.

In certain instances, the pain and swelling associated with an acuteattack of gout can be addressed with medications such as acetaminophen,steroids, nonsteroidal anti-inflammatory drugs (NSAIDs),adrenocorticotropic hormone (ACTH) or colchicine. In certain instances,proper medication controls gout within 12 to 24 hours and treatment isstopped after a few days. In certain instances, medication is used inconjunction with rest, increased fluid intake, ice-packs, elevationand/or protection of the affected area/s. In certain instances, theaforementioned treatments do not prevent recurrent attacks and they donot affect the underlying disorders of abnormal uric acid metabolism.

ii) Preventing Future Attacks.

In certain instances, reducing serum uric acid levels below thesaturation level is the goal for preventing further gout attacks. Insome cases, this is achieved by decreasing uric acid production (e.g.allopurinol), or increasing uric acid excretion with uricosuric agents(e.g. probenecid, sulfinpyrazone, benzbromarone).

In certain instances, allopurinol inhibits uric acid formation,resulting in a reduction in both the serum and urinary uric acid levelsand becomes fully effective after 2 to 3 months.

In certain instances, allopurinol is a structural analogue ofhypoxanthine, (differing only in the transposition of the carbon andnitrogen atoms at positions 7 and 8), which inhibits the action ofxanthine oxidase, the enzyme responsible for the conversion ofhypoxanthine to xanthine, and xanthine to uric acid. In certaininstances, it is metabolized to the corresponding xanthine analogue,alloxanthine (oxypurinol), which is also an inhibitor of xanthineoxidase. In certain instances, alloxanthine, though more potent ininhibiting xanthine oxidase, is less pharmaceutically acceptable due tolow oral bioavailability. In certain instances, fatal reactions due tohypersensitivity, bone marrow suppression, hepatitis, and vasculitishave been reported with Allopurinol. In certain instances, the incidenceof side effects may total 20% of all individuals treated with the drug.Treatment for disorders of uric acid metabolism has not evolvedsignificantly in the following two decades since the introduction ofallopurinol.

In certain instances, Uricosuric agents (e.g., probenecid,sulfinpyrazone, and benzbromarone) increase uric acid excretion. Incertain instances, probenecid causes an increase in uric acid secretionby the renal tubules and, when used chronically, mobilizes body storesof urate. In certain instances, 25-50% of individuals treated withprobenecid fail to achieve reduction of serum uric acid levels <6 mg/dL.In certain instances, insensitivity to probenecid results from drugintolerance, concomitant salicylate ingestion, and renal impairment. Incertain instances, one-third of the individuals develop intolerance toprobenecid. In certain instances, administration of uricosuric agentsalso results in urinary calculus, gastrointestinal obstruction, jaundiceand anemia.

Plumbism or “Saturnine Gout”

In certain instances, excessive exposure to lead (lead poisoning orplumbism) results in “saturnine gout,” a lead-induced hyperuricemia dueto lead inhibition of tubular urate transport causing decreased renalexcretion of uric acid. In certain instances, more than 50% ofindividuals suffering from lead nephropathy suffer from gout. In certaininstances, acute attacks of saturnine gout occur in the knee morefrequently than the big toe. In certain instances, renal disease is morefrequent and more severe in saturnine gout than in primary gout. Incertain instances, treatment consists of excluding the individual fromfurther exposure to lead, the use of chelating agents to remove lead,and control of acute gouty arthritis and hyperuricaemia. In certaininstances, saturnine gout is characterized by less frequent attacks thanprimary gout. In certain instances, lead-associated gout occurs inpre-menopausal women, an uncommon occurrence in non lead-associatedgout.

Lesch-Nyhan Syndrome

In certain instances, Lesch-Nyhan syndrome (LNS or Nyhan's syndrome)affects about one in 100,000 live births. In certain instances, LNS iscaused by a genetic deficiency of the enzyme hypoxanthine-guaninephosphoribosyltransferase (HGPRT). In certain instances, LNS is anX-linked recessive disease. In certain instances, LNS is present atbirth in baby boys. In certain instances, the disorder leads to severegout, poor muscle control, and moderate mental retardation, which appearin the first year of life. In certain instances, the disorder alsoresults in self-mutilating behaviors (e.g., lip and finger biting, headbanging) beginning in the second year of life. In certain instances, thedisorder also results in gout-like swelling in the joints and severekidney problems. In certain instances, the disorder leads neurologicalsymptoms include facial grimacing, involuntary writhing, and repetitivemovements of the arms and legs similar to those seen in Huntington'sdisease. The prognosis for individuals with LNS is poor. In certaininstances, the life expectancy of an untreated individual with LNS isless than about 5 years. In certain instances, the life expectancy of atreated individual with LNS is greater than about 40 years of age.

Hyperuricemia and Other Diseases

In certain instances, hyperuricemia is found in individuals withcardiovascular disease (CVD) and/or renal disease. In certain instances,hyperuricemia is found in individuals with prehypertension,hypertension, increased proximal sodium reabsorption, microalbuminuria,proteinuria, kidney disease, obesity, hypertriglyceridemia, lowhigh-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia,hypoadiponectinemia, peripheral, carotid and coronary artery disease,atherosclerosis, congenative heart failure, stroke, tumor lysissyndrome, endothelial dysfunction, oxidative stress, elevated reninlevels, elevated endothelin levels, and/or elevated C-reactive proteinlevels. In certain instances, hyperuricemia is found in individuals withobesity (e.g., central obesity), high blood pressure, hyperlipidemia,and/or impaired fasting glucose. In certain instances, hyperuricemia isfound in individuals with metabolic syndrome. In certain instances,gouty arthritis is indicative of an increased risk of acute myocardialinfarction. In some embodiments, administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidto an individual are useful for decreasing the likelihood of a clinicalevent associated with a disease or condition linked to hyperuricemia,including, but not limited to, prehypertension, hypertension, increasedproximal sodium reabsorption, microalbuminuria, proteinuria, kidneydisease, obesity, hypertriglyceridemia, low high-density lipoproteincholesterol, hyperinsulinemia, hyperleptinemia, hypoadiponectinemia,peripheral, carotid and coronary artery disease, atherosclerosis,congenative heart failure, stroke, tumor lysis syndrome, endothelialdysfunction, oxidative stress, elevated renin levels, elevatedendothelin levels, and/or elevated C-reactive protein levels.

One embodiment provides a method of treating or preventing a conditioncharacterized by abnormal tissue or organ levels of uric acid in anindividual comprising administering to the individual an effectiveamount of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. Another embodiment provides the methodwherein the condition is gout, a recurrent gout attack, gouty arthritis,hyperuricaemia, hypertension, a cardiovascular disease, coronary heartdisease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidneydisease, kidney stones, kidney failure, joint inflammation, arthritis,urolithiasis, plumbism, hyperparathyroidism, psoriasis, sarcoidosis,hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency or acombination thereof. Another embodiment provides the method wherein thecondition is gout.

Another embodiment provides the method further comprising administeringa second agent effective for the treatment of the gout. Anotherembodiment provides the method wherein the second agent is a URAT 1inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, axanthine oxidoreductase inhibitor, or combinations thereof. Anotherembodiment provides the method wherein the second agent is2-((5-bromo-4-(4-cyclopropyl-1-naphthalenyl)-4H-1,2,4-triazol-3-yl)thio)aceticacid, allopurinol, febuxostat, FYX-051, or combinations thereof.

In some embodiments,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidis administered to an individual suffering from a disease or conditionrequiring treatment with a diuretic. In some embodiments,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidis administered to an individual suffering from a disease or conditionrequiring treatment with a diuretic, wherein the diuretic causes renalretention of urate. In some embodiments, the disease or condition iscongestive heart failure or essential hypertension.

In some embodiments, administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidto an individual is useful for improving motility or improving qualityof life.

In some embodiments, administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidto an individual is useful for treating or decreasing the side effectsof cancer treatment.

In some embodiments, administration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidto an individual is useful for decreasing kidney toxicity of cis-platin.

Methods of Reducing Serum Uric Acid Levels

Provided herein, in some embodiments, are methods for reducing serumuric acid levels by administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments, a methodof reducing serum uric acid levels in a mammal comprises administering2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments, the mammal is a human. In someembodiments, a method of reducing serum uric acid levels in a humancomprises administering to the human 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid, or a pharmaceuticallyacceptable salt or ester thereof.

In some embodiments, a method for reducing serum uric acid levelscomprises administering less than 100 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments, the method comprises administering lessthan 50 mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments, the method ofreducing serum uric acid levels comprises administering less than 150mg, less than 125 mg, less than 100 mg, less than 90 mg, less than 80mg, less than 70 mg, less than 60 mg, less than 50 mg, less than 45 mg,less than 40 mg, less than 35 mg, less than 30 mg, less than 25 mg, lessthan 20 mg, less than 10 mg, or less than 5 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments, the method for reducing serum uric acidlevels comprises administering less than 2 mg or less than 1 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments, the method of reducing serum uric acid levelscomprises administering not more than 150 mg, not more than 125 mg, notmore than 100 mg, not more than 90 mg, not more than 80 mg, not morethan 70 mg, not more than 60 mg, not more than 50 mg, not more than 45mg, not more than 40 mg, not more than 35 mg, not more than 30 mg, notmore than 25 mg, not more than 20 mg, not more than 10 mg, or not morethan 5 mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments, the method forreducing serum uric acid levels comprises administering not more than 2mg or not more than 1 mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid.

In certain embodiments, a method for reducing serum uric acid levelscomprises administering about 40 mg of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments, themethod comprises administering about 20 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In other embodiments, the method comprises administering about 5mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In certain embodiments, the method ofreducing serum uric acid levels comprises administering about 150 mg,about 125 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, about60 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg,about 25 mg, about 20 mg, about 10 mg, or about 5 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments, the method for reducing serum uric acidlevels comprises administering about 4 mg, about 3 mg, about 2 mg, about1 mg or about 0.5 mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid.

In some embodiments, a method for reducing serum uric acid levelscomprises administering less than 100 mg per day of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments, the method comprises administering lessthan 50 mg per day of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments, the method ofreducing serum uric acid levels comprises administering less than 150 mgper day, less than 125 mg per day, less than 100 mg per day, less than90 mg per day, less than 80 mg per day, less than 70 mg per day, lessthan 60 mg per day, less than 50 mg per day, less than 45 mg per day,less than 40 mg per day, less than 35 mg per day, less than 30 mg perday, less than 25 mg per day, less than 20 mg per day, less than 10 mgper day, or less than 5 mg per day of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments, themethod for reducing serum uric acid levels comprises administering lessthan 2 mg per day or less than 1 mg per day of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments, the method of reducing serum uric acid levelscomprises administering not more than 150 mg per day, not more than 125mg per day, not more than 100 mg per day, not more than 90 mg per day,not more than 80 mg per day, not more than 70 mg per day, not more than60 mg per day, not more than 50 mg per day, not more than 45 mg per day,not more than 40 mg per day, not more than 35 mg per day, not more than30 mg per day, not more than 25 mg per day, not more than 20 mg per day,not more than 10 mg per day, or not more than 5 mg per day of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments, the method for reducing serum uric acidlevels comprises administering not more than 2 mg per day or not morethan 1 mg per day of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid.

In certain embodiments, a method for reducing serum uric acid levelscomprises administering about 40 mg per day of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments, the method comprises administering about 20mg per day of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In other embodiments, the method comprisesadministering about 5 mg per day of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments, themethod of reducing serum uric acid levels comprises administering about150 mg per day, about 125 mg per day, about 100 mg per day, about 90 mgper day, about 80 mg per day, about 70 mg per day, about 60 mg per day,about 50 mg per day, about 45 mg per day, about 40 mg per day, about 35mg per day, about 30 mg per day, about 25 mg per day, about 20 mg perday, about 10 mg per day, or about 5 mg per day of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments, the method for reducing serum uric acidlevels comprises administering about 4 mg per day, about 3 mg per day,about 2 mg per day, about 1 mg per day or about 0.5 mg per day of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by at least 0.3 mg/dL 24 hours afteradministration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 0.5 mg/dL 24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 0.8 mg/dL 24hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 1 mg/dL 24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 2 mg/dL 24hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 3 mg/dL 24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 4 mg/dL 24hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid.

In certain embodiments of a method for reducing serum uric acid levels,the serum uric acid levels are reduced by at least 0.5 mg/dL 48 hoursafter administration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In certain embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 0.8 mg/dL 48 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 1 mg/dL 48hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 2 mg/dL 48 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 3 mg/dL 48hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by at least 0.5 mg/dL 72 hours afteradministration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 0.8 mg/dL 72 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 1 mg/dL 72hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 2 mg/dL 72 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 3 mg/dL 72hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid.

In certain embodiments of a method for reducing serum uric acid levels,the serum uric acid levels are reduced by at least 0.5 mg/dL at 6 hours,12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48 hours, 54hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, or 120 hoursafter administration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 0.8 mg/dL at 6 hours, 12 hours, 18 hours, 24 hours, 30hours, 36 hours, 42 hours, 48 hours, 54 hours, 60 hours, 72 hours, 84hours, 96 hours, 108 hours, or 120 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 1 mg/dL at 6hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, or120 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 2 mg/dL at 6 hours, 12 hours, 18 hours, 24hours, 30 hours, 36 hours, 42 hours, 48 hours, 54 hours, 60 hours, 72hours, 84 hours, 96 hours, 108 hours, or 120 hours after administrationof 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 3 mg/dL at 6hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, or120 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 4 mg/dL at 6 hours, 12 hours, 18 hours, 24hours, 30 hours, 36 hours, 42 hours, 48 hours, 54 hours, 60 hours, 72hours, 84 hours, 96 hours, 108 hours, or 120 hours after administrationof 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by about 0.5 mg/dL 24 hours afteradministration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby about 0.8 mg/dL 24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 1 mg/dL 24 hoursafter administration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In certain embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby about 2 mg/dL 24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 3 mg/dL 24 hoursafter administration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid.

In certain embodiments of a method for reducing serum uric acid levels,the serum uric acid levels are reduced by about 0.5 mg/dL 48 hours afteradministration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby about 0.8 mg/dL 48 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 1 mg/dL 48 hoursafter administration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby about 2 mg/dL 48 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 3 mg/dL 48 hoursafter administration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by about 0.5 mg/dL 72 hours afteradministration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby about 0.8 mg/dL 72 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 1 mg/dL 72 hoursafter administration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In certain embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby about 2 mg/dL 72 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 3 mg/dL 72 hoursafter administration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid.

In certain embodiments of a method for reducing serum uric acid levels,the serum uric acid levels are reduced by about 0.5 mg/dL at 6 hours, 12hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48 hours, 54hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, or 120 hoursafter administration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby about 0.8 mg/dL at 6 hours, 12 hours, 18 hours, 24 hours, 30 hours,36 hours, 42 hours, 48 hours, 54 hours, 60 hours, 72 hours, 84 hours, 96hours, 108 hours, or 120 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 1 mg/dL at 6hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, or120 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by about 2 mg/dL at 6 hours, 12 hours, 18 hours, 24 hours,30 hours, 36 hours, 42 hours, 48 hours, 54 hours, 60 hours, 72 hours, 84hours, 96 hours, 108 hours, or 120 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 3 mg/dL at 6hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, or120 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by about 4 mg/dL at 6 hours, 12 hours, 18 hours, 24 hours,30 hours, 36 hours, 42 hours, 48 hours, 54 hours, 60 hours, 72 hours, 84hours, 96 hours, 108 hours, or 120 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid.

In certain embodiments of a method for reducing serum uric acid levels,the serum uric acid levels are reduced by at least 10% from baseline 24hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 15% from baseline 24 hours after administrationof 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 20% frombaseline 24 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 30% from baseline 24 hours after administrationof 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 40% frombaseline 24 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 50% from baseline 24 hours after administrationof 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 60% frombaseline 24 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 10%, at least 20%, at least 30%, at least 40%,at least 50%, or at least 60% from baseline 24 hours afteradministration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid.

In certain embodiments of a method for reducing serum uric acid levels,the serum uric acid levels are reduced by about 10% from baseline 48hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 20% from baseline 48 hours after administrationof 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 30% frombaseline 48 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 40% from baseline 48 hours after administrationof 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 50% frombaseline 48 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 10%, at least 20%, at least 30%, at least 40%,at least 50%, or at least 60% from baseline 48 hours afteradministration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid.

In certain embodiments of a method for reducing serum uric acid levels,the serum uric acid levels are reduced by at least 15% from baseline 72hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 20% from baseline 72 hours after administrationof 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 30% frombaseline 72 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 40% from baseline 72 hours after administrationof 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, at least 50%, or at least 60% from baseline 72 hours afteradministration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by at least 10% from baseline at 6hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, or120 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 15% from baseline at 6 hours, 12 hours, 18hours, 24 hours, 30 hours, 36 hours, 42 hours, 48 hours, 54 hours, 60hours, 72 hours, 84 hours, 96 hours, 108 hours, or 120 hours afteradministration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 20% from baseline at 6 hours, 12 hours, 18 hours, 24 hours,30 hours, 36 hours, 42 hours, 48 hours, 54 hours, 60 hours, 72 hours, 84hours, 96 hours, 108 hours, or 120 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 30% frombaseline at 6 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours,42 hours, 48 hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours,108 hours, or 120 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 40% frombaseline at 6 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours,42 hours, 48 hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours,108 hours, or 120 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 50% frombaseline at 6 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours,42 hours, 48 hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours,108 hours, or 120 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 60% frombaseline at 6 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours,42 hours, 48 hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours,108 hours, or 120 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid.

In certain embodiments of a method for reducing serum uric acid levels,the serum uric acid levels are reduced by about 15% from baseline 24hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by about 20% from baseline 24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 30% frombaseline 24 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by about 40% from baseline 24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 50% frombaseline 24 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by about 60% from baseline 24 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by about 10% from baseline 48 hoursafter administration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby about 15% from baseline 48 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 20% frombaseline 48 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by about 30% from baseline 48 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 40% frombaseline 48 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by about 50% from baseline 48 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 60% frombaseline 48 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by about 10% from baseline 72 hoursafter administration of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In certain embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby about 15% from baseline 72 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 20% frombaseline 72 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by about 30% from baseline 72 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 40% frombaseline 72 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by about 50% from baseline 72 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 60% frombaseline 72 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid.

In certain embodiments of a method for reducing serum uric acid levels,the serum uric acid levels are reduced by about 10% from baseline at 6hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, or120 hours after administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In some embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by about 15% from baseline at 6 hours, 12 hours, 18 hours,24 hours, 30 hours, 36 hours, 42 hours, 48 hours, 54 hours, 60 hours, 72hours, 84 hours, 96 hours, 108 hours, or 120 hours after administrationof 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 20% frombaseline at 6 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours,42 hours, 48 hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours,108 hours, or 120 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 30% frombaseline at 6 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours,42 hours, 48 hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours,108 hours, or 120 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 40% frombaseline at 6 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours,42 hours, 48 hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours,108 hours, or 120 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 50% frombaseline at 6 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours,42 hours, 48 hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours,108 hours, or 120 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 60% frombaseline at 6 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours,42 hours, 48 hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours,108 hours, or 120 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by about 70% frombaseline at 6 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours,42 hours, 48 hours, 54 hours, 60 hours, 72 hours, 84 hours, 96 hours,108 hours, or 120 hours after administration of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by at least 0.5 mg/dL 24 hours afteradministration of about 1 mg of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 0.5 mg/dL 48 hours after administration of about1 mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 0.5 mg/dL 72 hours after administration of about 1 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 1 mg/dL 24hours after administration of about 1 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 1 mg/dL 48hours after administration of about 1 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 1 mg/dL 72hours after administration of about 1 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by at least 0.5 mg/dL 24 hours afteradministration of about 2 mg of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 0.5 mg/dL 48 hours after administration of about2 mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 0.5 mg/dL 72 hours after administration of about 2 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 1 mg/dL 24hours after administration of about 2 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 1 mg/dL 48hours after administration of about 2 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 1 mg/dL 72hours after administration of about 2 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by at least 1 mg/dL 24 hours afteradministration of about 5 mg of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 1 mg/dL 48 hours after administration of about 5mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 1 mg/dL 72 hours after administration of about 5 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by at least 1 mg/dL 24 hours afteradministration of about 20 mg of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 1 mg/dL 48 hours after administration of about20 mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 1 mg/dL 72 hours after administration of about 20 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by at least 2 mg/dL 24 hours afteradministration of about 40 mg of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 2 mg/dL 48 hours after administration of about40 mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 1 mg/dL 72 hours after administration of about 40 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by at least 5% from baseline 24 hoursafter administration of about 1 mg of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 10% from baseline 48 hours after administrationof about 1 mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 15% from baseline 48 hours after administration of about 1mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by at least 8% from baseline 24 hoursafter administration of about 2 mg of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 10% from baseline 24 hours after administrationof about 2 mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 15% from baseline 24 hours after administration of about 2mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 10% from baseline 48 hours after administration of about 2mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In certain embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 15% from baseline 48 hours after administration of about 2mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 15% from baseline 72 hours after administration of about 2mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by at least 20% from baseline 24hours after administration of about 5 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 20% frombaseline 48 hours after administration of about 5 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 10% frombaseline 72 hours after administration of about 5 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by at least 40% from baseline 24hours after administration of about 20 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In certain embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 30% frombaseline 48 hours after administration of about 20 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid. In some embodiments of a method for reducing serum uric acidlevels, the serum uric acid levels are reduced by at least 20% frombaseline 72 hours after administration of about 20 mg of2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-yl thio)-2-methylpropanoicacid.

In some embodiments of a method for reducing serum uric acid levels, theserum uric acid levels are reduced by at least 50% from baseline afteradministration of about 40 mg of 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl thio)-2-methylpropanoic acid. In certain embodiments of amethod for reducing serum uric acid levels, the serum uric acid levelsare reduced by at least 40% from baseline 48 hours after administrationof about 40 mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid. In some embodiments of a method forreducing serum uric acid levels, the serum uric acid levels are reducedby at least 20% from baseline 72 hours after administration of about 40mg of 2-((3-(4-cyanonaphthalen-1-yl) pyridin-4-ylthio)-2-methylpropanoic acid.

Kits

The compounds, compositions and methods described herein provide kitsfor the treatment of disorders, such as the ones described herein. Thesekits comprise a compound, compounds or compositions described herein ina container and, optionally, instructions teaching the use of the kitaccording to the various methods and approaches described herein. Suchkits may also include information, such as scientific literaturereferences, package insert materials, clinical trial results, and/orsummaries of these and the like, which indicate or establish theactivities and/or advantages of the composition, and/or which describedosing, administration, side effects, drug interactions, or otherinformation useful to the health care provider. Such information may bebased on the results of various studies, for example, studies usingexperimental animals involving in vivo models and studies based on humanclinical trials. Kits described herein can be provided, marketed and/orpromoted to health providers, including physicians, nurses, pharmacists,formulary officials, and the like. Kits may also, in some embodiments,be marketed directly to the consumer.

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidcan be utilized for diagnostics and as research reagents. For example,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,either alone or in combination with other compounds, can be used astools in differential and/or combinatorial analyses to elucidateexpression patterns of genes expressed within cells and tissues. As onenon-limiting example, expression patterns within cells or tissuestreated with one or more compounds are compared to control cells ortissues not treated with compounds and the patterns produced areanalyzed for differential levels of gene expression as they pertain, forexample, to disease association, signaling pathway, cellularlocalization, expression level, size, structure or function of the genesexamined. These analyses can be performed on stimulated or unstimulatedcells and in the presence or absence of other compounds which affectexpression patterns.

Besides being useful for human treatment,2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidand formulations thereof, may be useful for veterinary treatment ofcompanion animals, exotic animals and farm animals, including mammals,rodents, and the like. More preferred animals include horses, dogs, andcats.

EXAMPLES

The examples and preparations provided below further illustrate andexemplify the present invention. The scope of the present invention isnot limited in any way by the scope of the following examples.

Example 1: Preparation of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwas prepared as described in U.S. provisional patent application61/355,491 and PCT/US11/40585 and as described below.

Step A

A mixture of 3-bromo-4-chloropyridine (10.0 g, 52 mmol) and sodiumsulfide (12.2 g, 156 mmol) in DMF (100 mL) was stirred at 130° C. for 2hours. The mixture was cooled in an ice water bath, and aqueous HCl (6N,45 mL) added dropwise with rigorous stirring. The resulting yellow pastewas concentrated using rotary evaporation on a water bath (80° C.) todryness. The resulting yellow solid was extracted with methanol (4×50mL), and the combined extracts concentrated to give a yellow solid (9.5g, 96%).

Step B

A mixture of 3-bromopyridine-4-thiol (step A, 4.75 g, 25 mmol), ethyl2-bromoisobutyrate (9.75 g, 50 mmol), and sodium carbonate (7.95 g, 75mmol) in DMF (50 mL) was stirred at 60° C. for 1 hour. The reactionmixture was partitioned between water (100 mL) and ethyl acetate (100mL). The organic layer was washed with water (2×100 mL) and saturatedsodium chloride (100 mL). The aqueous washes were back extracted withethyl acetate (2×100 mL). The combined organic layers were dried oversodium sulfate, concentrated, and purified by normal phasechromatography (0-25% ethyl acetate in hexane gradient) to yield ethyl2-(3-bromopyridin-4-ylthio)-2-methylpropanoate as a pale yellow oil (6.6g, 88%).

Step C

To a mixture of (4-cyanonaphthalen-1-yl) boronic acid and Pd(dppf)Cl₂were added a solution of ethyl2-((3-bromopyridin-4-ylthio)-2-methylpropanoate in THF, acetonitrile,and sodium carbonate. The resulting mixture was degassed by nitrogenbubbling for 1 minute, and heated to 150° C. for 30 minutes undermicrowave irradiation. The mixture was loaded on to a ISCO loadingcartridge and eluded with a gradient of 0-100% ethyl acetate in hexaneon a ISCO column to yield ethyl2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoate.

Step D

Methanol and sodium hydroxide were added to ethyl2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoate andstirred at ambient temperature for 2 hours. The volume was reduced byrotary evaporation. To the residue was added HCl (6 N aqueous) withstirring until pH 6, resulting in the formation of a white precipitate,which was isolated by filtration. The solid was washed with water, airdried and dried under vacuum (P₂O₅) overnight to yield2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.22 (bs, 1H), 8.61 (s, 1H), 8.34-8.39(m, 2H), 8.02 (dd, J=7.2, 7.2 Hz, 1H), 7.74-7.79 (m, 2H), 7.60 (dd,J=7.6, 7.6 Hz, 1H), 7.44-7.53 (m, 2H), 1.61 (s, 3H), 1.54 (s, 3H).

MS (m/z), M+1, 349.14

Example 2: Evaluation with URAT1-Model Assay

HEK293 human embryonic kidney cells (ATCC# CRL-1573) were propagated inEMEM tissue culture medium as described by ATCC in an atmosphere of 5%CO₂ and 95% air. Transfections of HEK293 cells with a model URAT1construct was performed using L2000 transfection reagent (Invitrogen) asdescribed by the manufacturer. After 24 h the transfected cells weresplit into 10 cm tissue culture plates and grown for 1 day after whichthe medium was replaced with fresh growth medium containing G418 (Gibco)at 0.5 mg/ml final concentration. Drug-resistant colonies were selectedafter approximately 8 days and then tested for ¹⁴C-uric acid transportactivity. The HEK293/URAT1-model cells are plated on Poly-D-LysineCoated 96-well Plates at a density of 125,000 cells per well.

Cells were grown overnight (20-26 hours) at 37° C. in an incubator.Plates were allowed to come to room temperature and media was washed outwith one wash of 250 μl of Wash Buffer (125 mM Na Gluconate, 10 mM Hepesph 7.3).2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidor vehicle is added in assay buffer with ¹⁴C-uric acid for a finalconcentration of 125 μM Uric Acid with a specific activity of 54mCi/mmol. Assay Buffer is 125 mM Sodium Gluconate, 4.8 mM PotassiumGluconate, 1.2 mM Potassium phosphate, monobasic, 1.2 mM magnesiumsulfate, 1.3 mM Ca Gluconate, 5.6 mM Glucose, 25 mM HEPES, pH 7.3.Plates were incubated at room temperature for 10 minutes then washed 3times with 50 μl Wash Buffer and 3 times with 250 μl Wash Buffer.Microscint 20 Scintillation Fluid was added and plates were incubatedovernight at room temperature to equilibrate. Plates are then read onthe TopCount Plate Reader and an EC50 value generated. (See Enomoto etal, Nature, 2002, 417, 447-451 and Anzai et al, J. Biol. Chem., 2004,279, 45942-45950.)

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwas tested according to the protocol described above against URAT-1model.2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidhas an EC₅₀ value ≤0.05 μM.

Example 3: Single-Dose Phase I Clinical Trial

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwas investigated according to the clinical trial described below.

Study

A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study toEvaluate Safety, Tolerability, Pharmacokinetics and Preliminary FoodEffect of Single Doses of a URAT1 Inhibitor, in Healthy Adult MaleVolunteers.

Objectives

To assess safety, tolerability, pharmacokinetics and uricosuric effectsafter oral administration as single doses of a tablet formulation andthe effect of food on bioavailability.

Investigational Plan/Study Design

Subjects receive a single, oral dose of active or placebo, at thefollowing doses:

Group 1: 2 mg (fasted);

Group 2: 5 mg (fasted);

Group 3: 5 mg (fed);

Group 4: 20 mg (fasted) [sentinel dosing];

Group 5: 20 mg (fed);

Group 6: 40 mg (fasted)

Study Details

Subjects

48 subjects in 6 dose groups, 8 subjects/group, are randomized 3:1 toreceive active (6/group) or placebo (2/group). All study procedures arethe same regardless of whether subject receives active or placebo. Thetotal duration of subject participation, including screening period, is˜2-4 weeks, and the total volume of blood collected from each subjectduring the entire study <500 mL, (less than typically collected during avolunteer blood donation).

Study Medication

5 mg and 20 mg, active and placebo, tablets packaged in 35 count HDPEbottles, stored at controlled room temperature (15-30° C.). Placebotablets are designed to match the active tablets—identical size, form,taste, and color, and containing the same excipients. 2 mg was dosed asan oral solution.

Participation Criteria

Inclusion Criteria:

Healthy male adults, age 18-45, with body weight >50 kg and BMI 18-30kg/m².

All laboratory parameters (chemistry, hematology, urinalysis) withinnormal limits; sUA≥5 mg/dL.

Subjects free of clinically significant disease and have normal physicalexamination, including normal blood pressure (90-140/50-90 mmHg), heartrate (50-100 bpm), body temp (35.0-37.5° C.) and respiratory rate (8-20bpm), and no electrocardiogram abnormalities.

Exclusion Criteria:

Any illness within 1 week of dosing, or HIV, Hep B or Hep C positive.

History of kidney stones, significant metabolic, hematological,pulmonary, cardiovascular, gastrointestinal, neurologic, hepatic, renal,urological, psychiatric disorders, cardiac abnormalities, or majorsurgery within past 3 months.

Donation of blood or plasma, or received an investigational therapywithin previous 3 months.

Any drug treatment, including prescribed/OTC medicines or herbalpreparations, in previous 14 days.

History of drug addiction, excessive alcohol use, heavy caffeinedrinker, use of tobacco products within previous 30 days, and/or refusalto abstain from tobacco, alcohol, caffeine during the study.

Refusal to refrain from strenuous exercise during study.

Subjects with allergies, or hypersensitivity to any ingredient in theinvestigational products.

Summary of Study Activities/Schedule of Events

FIG. 1A shows a schematic representation of the schedule of events.

Screening Visit Days −21 to −3

After obtaining written informed consent, subjects are screened toconfirm study eligibility.

Pretreatment: Day −2 to −1

Subjects are admitted to CRU ˜48 hours prior to dosing and remain at thecenter until all study assessments complete, with standardized mealsserved at appropriate times.

The following is performed on Day −1 beginning 24 hours pre-dose:

Urine (total catch) collected over the following intervals: −24 to −18,−18 to −12, −12 to 0 hours;

Serum samples collected at −24, −18 and −12 hrs.

Treatment Period: Days 1 to 4

The following is performed during the treatment period:

Subjects dosed on the morning of Day 1 with ˜240 mL of room temp water.

Fasted: subjects are dosed after overnight fast >10 hours and remainfasted until >4 hours post-dose.

Fed: subjects fast overnight for >10 hours, then are dosed 30 mins aftercompleting standard moderate fat breakfast (no high fructose cornsyrup).

Plasma samples are collected at:

−0.5 (pre dose);

0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 30, 36, 48,54, 60, and 72 hours (post-dose)

Additional plasma sample (20 mL) at 4 hours post-dose (metabolitetesting)

Urine samples (total catch) are collected over the following intervals:

0 to 6, 6 to 12, 12 to 24, 24 to 36, 36 to 48, 48 to 60, and 60 to 72hours post-dose.

Serum samples are collected at:

0 hours (within 30 minutes dosing), 6, 12, 24, 30, 36, 48, 54, 60 and 72hours post-dose.

PD samples are frozen (−20° C.) and stored; all samples from a givensubject assayed in a single analytical run.

End of Study

Subjects remain at the study site until all scheduled samples arecollected through the morning of Day 4. Upon completion of allstudy-related procedures and assessments, subjects discharged.

Subjects return to study site for follow-up visit on Day 8±1, forphysical exam, vital signs, ECG, safety laboratory tests, AEs andconcomitant medications.

Adverse Events, Serious Adverse Events and Removal from the Trial

An adverse event (AE) is any untoward medical occurrence associated withthe use of a drug, whether or not considered drug related. Adverseevents are continuously monitored throughout the study.

The severity of AEs should be identified as mild, moderate, severe orlife threatening. The relationship of the AE to the study medicationshould be identified as Not Related, Unlikely, or Possible.

A serious adverse event (SAE) is any AE that results in: death,life-threatening AE, hospitalization, a persistent or significantdisability/incapacity or substantial disruption of the ability toconduct normal life functions, or a congenital anomaly/birth defect.

A subject may be withdrawn for a protocol violation, a serious AE, aclinically significant change in a laboratory parameter or at therequest of the subject. Subjects withdrawing after dosing not replaced.

Evaluation of Results

Pharmacokinetics (PK), Pharmacodynamics (PD) and Safety & Adverse Eventsare evaluated. All dosed subjects who have evaluable PK data make up thePK Population. All dosed subjects make up the Safety Population. Allsampling times are in relation to the beginning of dosing (subjecttaking first tablet).

Example 4A: Single-Dose Clinical Trial Results for Group 1

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwas investigated according to the clinical trial described in Example 3.

Results for the eight subjects in Group 1 (2 mg, fasted) are shownbelow. Subjects 1 and 2 received placebo; subjects 3-8 received active.

Absolute sUA concentrations (mg/dL) from 0-72 hours post-dose are shownin the table below, and presented in graphical form in FIG. 2A.

Absolute sUA concentration (mg/dL) Subject number Mean Mean Time 1 2 3 45 6 7 8 Placebo (3-8) 0 8.1 6.0 7.4 7.3 6.6 6.3 6.2 5.1 7.1 6.5 6 8.56.2 6.6 6.6 6.0 5.9 5.1 4.7 7.4 5.8 12 8.0 5.8 6.4 6.3 5.6 5.5 4.9 4.26.9 5.5 24 8.0 6.2 6.8 6.4 5.9 6.2 5.7 4.7 7.1 6.0 30 7.7 5.7 6.5 6.35.6 5.7 5.3 4.3 6.7 5.6 36 7.2 5.5 6.3 6.1 5.2 5.3 4.8 4.0 6.4 5.3 487.4 5.5 6.8 6.4 5.4 5.8 5.1 4.3 6.5 5.6 54 6.7 5.0 6.5 5.9 5.1 5.2 4.84.0 5.9 5.3 60 6.5 4.9 6.6 5.9 5.0 4.9 4.6 3.8 5.7 5.1 72 6.9 5.3 6.56.1 5.3 5.8 5.0 4.2 6.1 5.5% sUA change (from baseline) from 0-72 hours post-dose are shown in thetable below, and presented in graphical form in FIG. 2B.

% sUA change (from baseline) Subject number Mean Mean Time 1 2 3 4 5 6 78 Placebo (3-8) 0 0 0 0 0 0 0 0 0 0 0 6 6.5 2.8 −30.4 −47.5 −35.5 −37.8−38.2 −33.3 4.1 −10.2 12 0 0 −44.6 −52.5 −48.4 −44.6 −43.4 −42.3 −2.3−15.6 24 8.1 4.2 −41.1 −44.1 −43.5 −40.5 −43.4 −46.2 1.1 −8.1 30 3.2−5.6 −46.4 −52.5 −43.5 −44.6 −44.7 −52.6 −5.0 −13.5 36 −8.1 −9.9 −48.2−52.5 −45.2 −45.9 −46.1 −52.6 −9.7 −18.8 48 −6.5 −7 −32.1 −42.4 −38.7−36.5 −35.5 −48.7 −8.5 −13.3 54 −1.6 −14.1 −33.9 −45.8 −37.1 −27 −32.9−48.7 −17.0 −19.3 60 −8.1 −18.3 −35.7 −45.8 −35.5 −29.7 −32.9 −46.2−19.1 −21.3 72 3.2 −11.3 −23.2 −30.5 −16.1 −14.9 −15.8 −28.2 −13.3 −15.5

Example 4B: Single-Dose Clinical Trial Results for Group 2

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwas investigated according to the clinical trial described in Example 3.

Results for the eight subjects in Group 2 (5 mg, fasted) are shownbelow. Subjects 1 and 2 received placebo; subjects 3-8 received active.

Absolute sUA concentrations (mg/dL) from 0-72 hours post-dose are shownin the table below.

Absolute sUA concentration (mg/dL) Subject Mean Mean Time 1 2 3 4 5 6 78 Placebo (3-8) 0 6.0 5.4 7.4 7.2 6.3 6.1 6.1 5.9 5.7 6.5 6 6.2 5.5 5.66.2 5.4 5.3 4.4 4.6 5.9 5.3 12 5.9 5.1 4.7 6.0 5.1 5.3 3.8 4.0 5.5 4.824 6.2 5.4 5.5 6.4 5.6 6.1 4.5 4.9 5.8 5.5 30 5.7 5.9 5.2 6.0 5.2 5.63.9 4.2 5.8 5.0 36 5.3 5.3 5.0 5.5 5.4 5.2 3.6 4.0 5.3 4.8 48 5.4 5.95.4 6.4 5.7 5.4 4.2 4.7 5.7 5.3 54 5.0 5.7 5.1 5.9 5.3 5.1 4.1 4.2 5.45.0 60 4.8 4.9 5.3 5.6 5.0 4.8 4.1 4.2 4.9 4.8 72 5.0 5.1 5.8 6.1 5.55.3 4.5 4.5 5.1 5.3% sUA change (from baseline) from 0-72 hours post-dose are shown in thetable below.

% sUA reduction (from baseline) Subject Mean Mean Time 1 2 3 4 5 6 7 8Placebo (3-8) 0 0 0 0 0 0 0 0 0 0 0 6 3.3 1.9 −24.3 −13.9 −14.3 −13.1−27.9 −22.0 2.6 −19.3 12 −1.7 −5.6 −36.5 −16.7 −19.0 −13.1 −37.7 −32.2−3.7 −25.9 24 3.3 0.0 −25.7 −11.1 −11.1 0.0 −26.2 −16.9 1.7 −15.2 30−5.0 9.3 −29.7 −16.7 −17.5 −8.2 −36.1 −28.8 2.2 −22.8 36 −11.7 −1.9−32.4 −23.6 −14.3 −14.8 −41.0 −32.2 −6.8 −26.4 48 −10.0 9.3 −27.0 −11.1−9.5 −11.5 −31.1 −20.3 −0.4 −18.4 54 −16.7 5.6 −31.1 −18.1 −15.9 −16.4−32.8 −28.8 −5.6 −23.9 60 −20.0 −9.3 −28.4 −22.2 −20.6 −21.3 −32.8 −28.8−14.7 −25.7 72 −16.7 −5.6 −21.6 −15.3 −12.7 −13.1 −26.2 −23.7 −11.2−18.8

Example 4C: Single-Dose Clinical Trial Results for Group 3

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwas investigated according to the clinical trial described in Example 3.

Results for the eight subjects in Group 3 (5 mg, fed) are shown below.Subjects 1 and 2 received placebo; subjects 3-8 received active.

Absolute sUA concentrations (mg/dL) from 0-72 hours post-dose are shownin the table below.

Absolute sUA concentration (mg/dL) Subject Mean Mean Time 1 2 3 4 5 6 78 Placebo (3-8) 0 6.2 6.0 6.9 6.6 6.5 6.0 5.7 4.0 6.1 6.0 6 5.9 5.4 4.44.5 4.5 4.4 2.8 5.7 4.1 12 5.4 5.1 4.1 4.1 4.6 4.5 4.4 2.5 5.3 4.0 246.2 5.8 5.0 5.1 5.2 5.5 5.3 3.3 6.0 4.9 30 5.6 5.3 4.6 4.6 4.7 5.1 4.72.8 5.5 4.4 36 5.3 5.0 4.3 4.4 4.6 4.9 4.5 2.6 5.2 4.2 48 5.6 4.6 4.74.6 5.0 4.6 4.9 2.9 5.1 4.5 54 5.0 5.0 4.3 3.5 4.7 3.7 4.5 2.7 5.0 3.960 4.9 4.6 5.0 4.7 4.5 4.8 4.3 2.6 4.8 4.3 72 5.4 4.8 5.9 5.4 5.2 5.34.8 3.0 5.1 4.9% sUA change (from baseline) from 0-72 hours post-dose are shown in thetable below.

% sUA reduction (from baseline) Subject Mean Mean Time 1 2 3 4 5 6 7 8Placebo (3-8) 0 0 0 0 0 0 0 0 0 0 0 6 −4.8 −10.0 −36.2 −31.8 −25.0 −22.8−30.0 −7.4 −29.2 12 −12.9 −15.0 −40.6 −37.9 −29.2 −25.0 −22.8 −37.5−14.0 −32.2 24 0.0 −3.3 −27.5 −22.7 −20.0 −8.3 −7.0 −17.5 −1.7 −17.2 30−9.7 −11.7 −33.3 −30.3 −27.7 −15.0 −17.5 −30.0 −10.7 −25.6 36 −14.5−16.7 −37.7 −33.3 −29.2 −18.3 −21.1 −35.0 −15.6 −29.1 48 −9.7 −23.3−31.9 −30.3 −23.1 −23.3 −14.0 −27.5 −16.5 −25.0 54 −19.4 −16.7 −37.7−47.0 −27.7 −38.3 −21.1 −32.5 −18.1 −34.1 60 −21.0 −23.3 −27.5 −28.8−30.8 −20.0 −24.6 −35.0 −22.2 −27.8 72 −12.9 −20.0 −14.5 −18.2 −20.0−11.7 −15.8 −25.0 −16.5 −17.5Absolute sUA (mg/dL) and % sUA change from 0-72 hours post-dose forgroups 2 and 3, are presented in graphical form in FIGS. 3A and 3Brespectively.

Example 4D: Single-Dose Clinical Trial Results for Group 4

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwas investigated according to the clinical trial described in Example 3.

Results for the eight subjects in Group 4 (20 mg, fasted) are shownbelow. Subjects 1 and 2 received placebo; subjects 3-8 received active.

Absolute sUA concentrations (mg/dL) from 0-72 hours post-dose are shownin the table below.

Absolute sUA concentration (mg/dL) Subject Mean Mean Time 1 2 3 4 5 6 78 Placebo (3-8) 0 7.1 6.2 7.8 7.6 7.4 6.2 5.9 5.6 6.7 6.8 6 7.3 6.6 5.24.7 4.6 4.0 3.1 3.9 7.0 4.3 12 7.1 4.1 4.5 4.3 6.2 3.2 2.8 3.1 5.6 4.024 7.4 6.7 4.2 4.3 4.4 3.5 3.3 3.3 7.1 3.8 30 6.7 6.4 3.7 4.2 4.1 3.52.8 3.0 6.6 3.6 36 6.4 5.7 3.7 4.1 4.0 3.4 2.8 2.9 6.1 3.5 48 6.6 5.84.0 4.9 4.7 3.8 3.4 3.8 6.2 4.1 54 6.1 6.1 4.0 5.1 5.4 3.9 3.2 3.7 6.14.2 60 5.8 5.7 4.2 5.1 5.2 4.0 3.2 3.6 5.8 4.2 72 6.3 6.4 5.6 6.4 6.35.2 4.1 4.3 6.4 5.3% sUA change (from baseline) from 0-72 hours post-dose are shown in thetable below.

% sUA reduction (from baseline) Subject Mean Mean Time 1 2 3 4 5 6 7 8Placebo (3-8) 0 0 0 0 0 0 0 0 0 0 0 6 2.8 6.5 −33.3 −38.2 −37.8 −35.5−47.5 −30.4 4.7 −37.1 12 0.0 −33.9 −42.3 −43.4 −16.2 −48.4 −52.5 −44.6−17.0 −41.2 24 4.2 8.1 −46.2 −43.4 −40.5 −43.5 −44.1 −41.1 6.2 −43.1 30−5.6 3.2 −52.6 −44.7 −44.6 −43.5 −52.5 −46.4 −1.2 −47.4 36 −9.9 −8.1−52.6 −46.1 −45.9 −45.2 −52.5 −48.2 −9.0 −48.4 48 −7.0 −6.5 −48.7 −35.5−36.5 −38.7 −42.4 −32.1 −6.8 −39.0 54 −14.1 −1.6 −48.7 −32.9 −27.0 −37.1−45.8 −33.9 −7.9 −37.6 60 −18.3 −8.1 −46.2 −32.9 −29.7 −35.5 −45.8 −35.7−13.2 −37.6 72 −11.3 3.2 −28.2 −15.8 −14.9 −16.1 −30.5 −23.2 −4.1 −21.5

Example 4E: Single-Dose Clinical Trial Results for Group 5

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwas investigated according to the clinical trial described in Example 3.

Results for the eight subjects in Group 5 (20 mg, fed) are shown below.Subjects 1 and 2 received placebo; subjects 3-8 received active.

Absolute sUA concentrations (mg/dL) from 0-72 hours post-dose are shownin the table below.

Absolute sUA concentration (mg/dL) Subject Mean Mean Time 1 2 3 4 5 6 78 Placebo (3-8) 0 6.7 5.6 8.1 7.8 7.6 6.4 6.3 6.1 6.2 7.1 6 6.4 5.4 5.04.2 3.5 3.6 3.6 3.5 5.9 3.9 12 6.0 5.1 4.0 3.7 2.4 2.5 3.0 2.8 5.6 3.124 7.0 5.6 4.5 4.6 3.1 3.2 3.5 3.8 6.3 3.8 30 6.3 5.1 4.3 4.2 3.3 3.03.2 3.9 5.7 3.7 36 6.0 4.8 4.1 4.0 3.3 3.0 3.0 3.7 5.4 3.5 48 6.5 5.14.8 4.8 4.7 3.7 3.6 4.7 5.8 4.4 54 6.1 4.8 4.6 4.8 4.7 3.7 3.6 4.4 5.54.3 60 5.6 4.5 4.5 4.7 4.7 3.5 3.5 4.3 5.1 4.2 72 6.0 4.9 5.3 5.5 5.64.5 4.2 5.0 5.5 5.0% sUA change (from baseline) from 0-72 hours post-dose are shown in thetable below.

% sUA reduction (from baseline) Subject Mean Mean Time 1 2 3 4 5 6 7 8Placebo (3-8) 0 0 0 0 0 0 0 0 0 0 0 6 −4.5 −3.6 −38.3 −46.2 −53.9 −43.8−42.9 −42.6 −4.05 −44.6 12 −10.4 −8.9 −50.6 −52.6 −68.4 −60.9 −52.4−54.1 −9.65 −56.5 24 4.5 0.0 −44.4 −41.0 −59.2 −50.0 −44.4 −37.7 2.25−46.1 30 −6.0 −8.9 −46.9 −46.2 −56.6 −53.1 −49.2 −36.1 −7.45 −48 36−10.4 −14.3 −49.4 −48.7 −56.6 −53.1 −52.4 −39.3 −12.4 −49.9 48 −3.0 −8.9−40.7 −38.5 −38.2 −42.2 −42.9 −23.0 −5.95 −37.6 54 −9.0 −14.3 −43.2−38.5 −38.2 −42.2 −42.9 −27.9 −11.7 −38.8 60 −16.4 −19.6 −44.4 −39.7−38.2 −45.3 −44.4 −29.5 −18 −40.3 72 −10.4 −12.5 −34.6 −29.5 −26.3 −29.7−33.3 −18.0 −11.5 −28.6Absolute sUA (mg/dL) and % sUA change from 0-72 hours post-dose forgroups 4 and 5, are presented in graphical form in FIGS. 4A and 4Brespectively.

Example 4F: Single-Dose Clinical Trial Results for Group 6

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwas investigated according to the clinical trial described in Example 3.

Results for the eight subjects in Group 6 (40 mg, fasted) are shownbelow. Subjects 1 and 2 received placebo; subjects 3-8 received active.

Absolute sUA concentrations (mg/dL) from 0-72 hours post-dose are shownin the table below, and presented in graphical form in FIG. 5A.

Absolute sUA concentration (mg/dL) Subject number Mean Mean Time 1 2 3 45 6 7 8 Placebo (3-8) 0 6.9 6.0 7.6 7.4 6.8 6.1 5.9 5.7 6.5 6.6 6 7.26.1 5.8 3.6 4.2 2.8 3.0 3.3 6.7 3.8 12 6.7 5.7 4.5 2.3 3.2 2.2 1.8 2.36.2 2.7 24 7.4 6.4 4.0 2.7 3.3 2.7 1.7 2.5 6.9 2.8 30 6.7 5.8 3.5 2.52.8 2.7 1.5 2.6 6.3 2.6 36 5.9 5.4 3.1 2.5 2.7 2.7 1.5 2.7 5.7 2.5 485.9 5.7 3.5 3.7 3.5 3.8 2.6 3.1 5.8 3.4 54 5.8 5.3 3.3 3.9 3.4 3.7 2.73.4 5.6 3.4 60 5.5 4.9 3.3 3.7 3.5 3.7 2.8 3.6 5.2 3.4 72 6.5 5.3 4.55.1 4.5 4.9 4.1 4.6 5.9 4.6% sUA change (from baseline) from 0-72 hours post-dose are shown in thetable below, and presented in graphical form in FIG. 5B.

% sUA change (from baseline) Subject number Mean Mean Time 1 2 3 4 5 6 78 Placebo (3-8) 0 0 0 0 0 0 0 0 0 0 0 6 4.3 1.7 −23.7 −51.4 −38.2 −54.1−49.2 −42.1 3.0 −43.1 12 −2.9 −5.0 −40.8 −68.9 −52.9 −63.9 −69.5 −59.6−4.0 −59.3 24 7.2 6.7 −47.4 −63.5 −51.5 −55.7 −71.2 −56.1 7.0 −57.6 30−2.9 −3.3 −53.9 −66.2 −58.8 −55.7 −74.6 −54.4 −3.1 −60.6 36 −14.5 −10.0−59.2 −66.2 −60.3 −55.7 −74.6 −52.6 −12.3 −61.4 48 −14.5 −5.0 −53.9−50.0 −48.5 −37.7 −55.9 −45.6 −9.8 −48.6 54 −15.9 −11.7 −56.6 −47.3−50.0 −39.3 −54.2 −40.4 −13.8 −48.0 60 −20.3 −18.3 −56.6 −50.0 −48.5−39.3 −52.5 −36.8 −19.3 −47.3 72 −5.8 −11.7 −40.8 −31.1 −33.8 −19.7−30.5 −19.3 −8.8 −29.2Absolute sUA and % sUA change from 0-72 hours post-dose for groups 1, 2,4 and 6 (2 mg, 5 mg, 20 mg and 40 mg, all fasted) are presented ingraphical form in FIGS. 6A and 6B, respectively.

Example 5: Multi-Dose Phase I Clinical Trial

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwas investigated according to the clinical trial described below.

Study

A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study toEvaluate Safety, Tolerability, Pharmacokinetics and Preliminary FoodEffect of Multiple Rising Doses of a URAT1 Inhibitor, in Healthy AdultMale Volunteers.

Investigational Plan/Study Design

Fasted subjects receive oral doses of active or placebo, once daily, for10 days, at the following doses:

Group 7: 1 mg

Group 8: 5 mg

Group 9: 10 mg

Study Details

Subjects

36 subjects in 3 dose groups, 12 subjects/group, are randomized 4:1 toreceive active (9/group) or placebo (2/group). All study procedures arethe same regardless of whether subject receives active or placebo. Totalduration of subject participation, including screening period, is ˜2-4weeks, and the total volume of blood collected from each subject duringthe entire study <500 mL, (less than typically collected during avolunteer blood donation).

Study Medication

5 mg, active and placebo, tablets packaged in 35 count HDPE bottles,stored at controlled room temperature (15-30° C.). Placebo tablets aredesigned to match the active tablets—identical size, form, taste, andcolor, and containing the same excipients. 1 mg doses were administeredas oral solutions.

Participation Criteria

Inclusion Criteria:

Healthy male adults, age 18-45, with body weight >50 kg and BMI 18-30kg/m².

All laboratory parameters (chemistry, hematology, urinalysis) withinnormal limits; sUA≥5 mg/dL.

Subjects free of clinically significant disease and have normal physicalexamination, including normal blood pressure (90-140/50-90 mmHg), heartrate (50-100 bpm), body temp (35.0-37.5° C.) and respiratory rate (8-20bpm), and no electrocardiogram abnormalities.

Exclusion Criteria:

Any illness within 1 week of dosing, or HIV, Hep B or Hep C positive.

History of kidney stones, significant metabolic, hematological,pulmonary, cardiovascular, gastrointestinal, neurologic, hepatic, renal,urological, psychiatric disorders, cardiac abnormalities, or majorsurgery within past 3 months.

Donation of blood or plasma, or received an investigational therapywithin previous 3 months.

Any drug treatment, including prescribed/OTC medicines or herbalpreparations, in previous 14 days.

History of drug addiction, excessive alcohol use, heavy caffeinedrinker, use of tobacco products within previous 30 days, and/or refusalto abstain from tobacco, alcohol, caffeine during the study.

Refusal to refrain from strenuous exercise during study.

Subjects with allergies, or hypersensitivity to any ingredient in theinvestigational products.

Summary of Study Activities/Schedule of Events

FIG. 1B shows a schematic representation of the schedule of events.

Screening Visit Days −21 to −3

After obtaining written informed consent, subjects screened to confirmstudy eligibility.

Pretreatment: Day −2 to −1

Subjects admitted to CRU ˜48 hours prior to dosing and remain at thecenter until all study assessments complete, with standardized mealsserved at appropriate times.

Urine, serum and plasma samples collected Day −1 beginning 24 hourspre-dose.

Treatment Period: Days 1 to 13

The following performed during the treatment period:

Subjects dosed in the morning of Days 1-10 with ˜240 mL of room tempwater.

Urine, serum and plasma samples collected periodically

PD samples frozen (−20° C.) and stored; all samples from a given subjectassayed in a single analytical run.

End of Study

Subjects remain at the study site until all scheduled samples arecollected through the morning of Day 13. Upon completion of allstudy-related procedures and assessments, subjects discharged.

Subjects return to study site for follow-up visit on Day 17±1, forphysical exam, vital signs, ECG, safety laboratory tests, AEs andconcomitant medications.

Adverse Events, Serious Adverse Events and Removal from the Trail

An adverse event (AE) is any untoward medical occurrence associated withthe use of a drug, whether or not considered drug related. Adverseevents are continuously monitored throughout the study.

The severity of AEs should be identified as mild, moderate, severe orlife threatening. The relationship of the AE to the study medicationshould be identified as Not Related, Unlikely, or Possible.

A serious adverse event (SAE) is any AE that results in: death,life-threatening AE, hospitalization, a persistent or significantdisability/incapacity or substantial disruption of the ability toconduct normal life functions, or a congenital anomaly/birth defect.

A subject may be withdrawn for a protocol violation, a serious AE, aclinically significant change in a laboratory parameter or at therequest of the subject. Subjects withdrawing after dosing not replaced.

Evaluation of Results

Pharmacokinetics (PK), Pharmacodynamics (PD) and Safety & Adverse Eventsare evaluated. All dosed subjects who have evaluable PK data make up thePK Population. All dosed subjects make up the Safety Population. Allsampling times are in relation to the beginning of dosing (subjecttaking first tablet).

Example 6A: Multi-Dose Clinical Trial Results for Group 7

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwas evaluated according to the clinical trial described above in Example5.

Results for twelve subjects in group 7, receiving 1 mg active orplacebo, once daily for 10 days, are shown below. Subjects 1, 2 and 3received placebo; subjects 4-12 received active.

Absolute sUA concentrations (mg/dL) by nominal timepoint (i.e. days0-9—once daily dosing, plus days 10-13, post dosing) are shown in thetable below, and presented in graphical form in FIG. 7A.

Absolute sUA concentration (mg/dL) Subject Number Mean Mean Time 1 2 3 45 6 7 8 9 10 11 12 Placebo (4-12) 0 7.3 6.6 6.2 7.0 6.9 6.7 6.2 6.0 5.95.8 5.6 5.4 6.7 6.2 6 7.3 6.5 6.4 6.9 6.8 6.7 6.2 5.3 5.8 5.5 5.5 5.26.7 6.0 12 7.1 6.1 6.1 6.6 6.4 6.1 6.1 5.0 5.3 5.1 5.0 4.9 6.4 5.6 247.4 6.9 6.1 7.1 6.6 6.8 6.7 5.8 6.0 5.8 5.9 5.5 6.8 6.2 48 7.0 5.8 4.46.0 5.8 5.4 5.5 4.7 4.9 5.1 3.6 4.8 5.7 5.1 72 7.9 6.8 6.5 7.0 6.6 6.26.2 5.5 5.9 5.3 5.6 5.3 7.1 6.0 96 7.9 6.5 6.2 6.7 6.7 6.1 6.0 5.0 5.55.0 5.1 5.1 6.9 5.7 102 7.7 6.3 6.2 6.2 6.2 5.9 5.7 4.6 5.4 4.4 4.9 4.96.7 5.4 108 7.3 5.9 5.5 6.1 5.9 5.4 5.6 4.3 5.0 4.1 4.4 4.8 6.2 5.1 1207.7 6.2 6.1 6.6 6.2 6.2 5.8 5.0 5.6 4.6 5.0 4.9 6.7 5.5 144 7.6 6.3 5.96.5 6.2 6.1 5.8 5.0 5.5 4.6 5.0 4.8 6.6 5.5 168 8.0 6.6 6.6 7.2 6.8 6.36.5 5.4 6.2 5.2 5.8 5.6 7.1 6.1 192 7.4 6.1 6.0 6.5 6.1 5.9 5.6 5.1 5.54.6 5.0 4.9 6.5 5.5 216 7.5 6.0 5.6 6.1 5.8 5.3 5.6 4.9 5.9 4.7 4.9 4.76.4 5.3 222 7.7 6.3 6.1 6.3 5.9 5.8 5.4 5.0 5.5 4.7 5.2 4.9 6.7 5.4 2287.4 6.1 5.7 6.2 5.6 5.5 5.3 4.8 5.4 4.3 4.8 4.9 6.4 5.2 240 7.8 6.7 5.96.9 6.2 6.2 5.9 5.2 6.0 4.8 5.5 5.3 6.8 5.8 246 7.3 6.1 5.4 6.4 5.8 5.65.7 5.1 5.5 4.4 4.8 4.9 6.3 5.4 252 7.3 5.8 5.6 6.9 6.1 5.9 5.9 5.0 5.44.5 5.0 5.0 6.2 5.5 264 7.5 5.8 5.6 6.4 6.2 6.0 5.7 5.1 5.7 4.5 5.1 5.16.3 5.5 270 6.9 5.1 5.1 6.0 5.9 5.4 5.3 4.7 5.1 4.1 4.6 4.8 5.7 5.1 2886.6 4.9 5.0 6.0 5.8 5.4 5.2 4.4 4.9 3.9 4.5 4.5 5.5 5.0 312 6.9 5.4 5.46.2 6.1 5.6 5.4 4.9 5.4 4.4 4.7 4.6 5.9 5.3 Timepoint in bold = dosingtimepoints Timepoints 222 and greater = post dosing% sUA change (from baseline) by nominal timepoint (i.e. days 0-9—oncedaily dosing, plus days 10-13, post dosing) are shown in the tablebelow, and presented in graphical form in FIG. 7B.

% sUA change (from baseline) Subject Number Mean Mean Time 1 2 3 4 5 6 78 9 10 11 12 Placebo (4-12) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 6 0.0 −1.5 3.2−1.4 −1.4 0.0 0.0 −11.7 −1.7 −5.2 −1.8 −3.7 0.6 −3.0 12 −2.7 −7.6 −1.6−5.7 −7.2 −9.0 −1.6 −16.7 −10.2 −12.1 −10.7 −9.3 −4.0 −9.2 24 1.4 4.5−1.6 1.4 −4.3 1.5 8.1 −3.3 1.7 0.0 5.4 1.9 1.4 1.4 48 −4.1 −12.1 −29.0−14.3 −15.9 −19.4 −11.3 −21.7 −16.9 −12.1 −35.7 −11.1 −15.1 −17.6 72 8.23.0 4.8 0.0 −4.3 −7.5 0.0 −8.3 0.0 −8.6 0.0 −1.9 5.3 −3.4 96 8.2 −1.50.0 −4.3 −2.9 −9.0 −3.2 −16.7 −6.8 −13.8 −8.9 −5.6 2.2 −7.9 102 5.5 −4.50.0 −11.4 −10.1 −11.9 −8.1 −23.3 −8.5 −24.1 −12.5 −9.3 0.3 −13.2 108 0.0−10.6 −11.3 −12.9 −14.5 −19.4 −9.7 −28.3 −15.3 −29.3 −21.4 −11.1 −7.3−18.0 120 5.5 −6.1 −1.6 −5.7 −10.1 −7.5 −6.5 −16.7 −5.1 −20.7 −10.7 −9.3−0.7 −10.3 144 4.1 −4.5 −4.8 −7.1 −10.1 −9.0 −6.5 −16.7 −6.8 −20.7 −10.7−11.1 −1.7 −11.0 168 9.6 0.0 6.5 2.9 −1.4 −6.0 4.8 −10.0 5.1 −10.3 3.63.7 5.4 −0.8 192 1.4 −7.6 −3.2 −7.1 −11.6 −11.9 −9.7 −15.0 −6.8 −20.7−10.7 −9.3 −3.1 −11.4 216 2.7 −9.1 −9.7 −12.9 −15.9 −20.9 −9.7 −18.3 0.0−19.0 −12.5 −13.0 −5.4 −13.6 222 5.5 −4.5 −1.6 −10.0 −14.5 −13.4 −12.9−16.7 −6.8 −19.0 −7.1 −9.3 −0.2 −12.2 228 1.4 −7.6 −8.1 −11.4 −18.8−17.9 −14.5 −20.0 −8.5 −25.9 −14.3 −9.3 −4.8 −15.6 240 6.8 1.5 −4.8 −1.4−10.1 −7.5 −4.8 −13.3 1.7 −17.2 −1.8 −1.9 1.2 −6.3 246 0.0 −7.6 −12.9−8.6 −15.9 −16.4 −8.1 −15.0 −6.8 −24.1 −14.3 −9.3 −6.8 −13.2 252 0.0−12.1 −9.7 −1.4 −11.6 −11.9 −4.8 −16.7 −8.5 −22.4 −10.7 −7.4 −7.3 −10.6264 2.7 −12.1 −9.7 −8.6 −10.1 −10.4 −8.1 −15.0 −3.4 −22.4 −8.9 −5.6 −6.4−10.3 270 −5.5 −22.7 −17.7 −14.3 −14.5 −19.4 −14.5 −21.7 −13.6 −29.3−17.9 −11.1 −15.3 −17.4 288 −9.6 −25.8 −19.4 −14.3 −15.9 −19.4 −16.1−26.7 −16.9 −32.8 −19.6 −16.7 −18.3 −19.8 312 −5.5 −18.2 −12.9 −11.4−11.6 −16.4 −12.9 −18.3 −8.5 −24.1 −16.1 −14.8 −12.2 −14.9 Timepoint inbold = dosing timepoints Timepoints 222 and greater = post dosing

Example 6B: Multi-Dose Clinical Trial Results for Group 8

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwas evaluated according to the clinical trial described above in Example5.

Results for ten subjects in group 8, receiving 5 mg active or placebo,once daily for 10 days, are shown below. Subjects 1, 2 and 3 receivedplacebo; subjects 4-10 received active.

Absolute sUA concentrations (mg/dL) by nominal timepoint (i.e. days0-9—once daily dosing, plus days 10-13, post dosing) are shown in thetable below, and presented in graphical form in FIG. 8A.

Absolute sUA concentration (mg/dL) Subject Number Mean Mean Time 1 2 3 45 6 7 8 9 10 Placebo (4-10) 0 6.5 6.3 5.4 6.5 6.5 6.0 5.8 5.6 5.5 5.36.1 5.9 6 6.9 6.6 5.8 5.3 5.3 4.8 4.8 4.3 3.8 4.5 6.4 4.7 12 6.7 6.2 5.45.2 5.3 4.5 4.6 3.9 3.3 4.0 6.1 4.4 24 6.7 6.3 5.2 5.3 5.6 5.0 5.4 4.23.4 3.8 6.1 4.7 48 7.4 6.5 5.6 5.2 4.1 4.4 5.1 3.7 3.1 3.0 6.5 4.1 727.1 5.9 5.3 4.5 4.2 4.3 4.7 3.5 3.0 3.2 6.1 3.9 96 8.0 6.3 5.7 4.6 4.34.2 4.8 3.7 3.5 3.6 6.7 4.1 102 8.0 6.8 6.0 4.1 3.7 3.8 4.2 3.1 3.0 3.76.9 3.7 108 7.2 6.2 5.5 4.4 3.8 3.4 4.0 2.9 2.8 3.4 6.3 3.5 120 7.4 6.65.6 4.9 4.4 4.3 4.6 3.9 3.1 3.7 6.5 4.1 144 8.0 6.3 6.1 4.4 4.0 3.7 4.43.6 3.3 3.3 6.8 3.8 168 6.8 5.9 5.5 4.1 3.6 3.7 4.4 3.5 3.3 2.9 6.1 3.6192 7.3 6.0 5.5 4.4 3.8 3.6 4.8 3.6 3.1 3.2 6.3 3.8 216 7.5 6.1 6.6 4.44.4 3.9 4.4 3.3 4.1 3.0 6.7 3.9 222 7.6 6.7 6.8 4.0 3.9 3.7 3.9 3.1 3.23.1 7.0 3.6 228 7.1 6.2 6.3 4.1 3.9 3.4 3.7 3.1 3.2 2.8 6.5 3.5 240 6.96.4 6.4 4.7 4.5 4.0 4.3 4.1 3.6 3.2 6.6 4.1 246 6.3 5.7 5.9 4.4 4.0 3.84.1 3.9 3.3 3.0 6.0 3.8 252 5.8 5.3 5.4 4.2 3.7 3.3 4.0 3.8 3.2 2.9 5.53.6 264 5.7 5.3 5.7 4.4 4.0 4.0 4.2 4.1 4.0 3.3 5.6 4.0 270 5.6 5.3 5.55.0 4.4 4.5 5.0 4.7 4.0 4.1 5.5 4.5 288 5.7 5.4 5.5 4.9 4.3 4.1 4.8 4.84.2 3.8 5.5 4.4 312 5.6 6.1 5.8 5.6 4.7 4.9 5.5 5.2 4.9 4.6 5.8 5.1Timepoint in bold = dosing timepoints Timepoints 222 and greater = postdosing% sUA change (from baseline) by nominal timepoint (i.e. days 0-9—oncedaily dosing, plus days 10-13, post dosing) are shown in the tablebelow, and presented in graphical form in FIG. 8B.

% sUA change (from baseline) Subject Number Mean Mean Time 1 2 3 4 5 6 78 9 10 Placebo (4-12) 0 0 0 0 0 0 0 0 0 0 0 0 0 6 6.2 4.8 7.4 −18.5−18.5 −20.0 −17.2 −23.2 −30.9 −15.1 6.1 −20.5 12 3.1 −1.6 0.0 −20.0−18.5 −25.0 −20.7 −30.4 −40.0 −24.5 0.5 −25.6 24 3.1 0.0 −3.7 −18.5−13.8 −16.7 −6.9 −25.0 −38.2 −28.3 −0.2 −21.1 48 13.8 3.2 3.7 −20.0−36.9 −26.7 −12.1 −33.9 −43.6 −43.4 6.9 −30.9 72 9.2 −6.3 −1.9 −30.8−35.4 −28.3 −19.0 −37.5 −45.5 −39.6 0.3 −33.7 96 23.1 0.0 5.6 −29.2−33.8 −30.0 −17.2 −33.9 −36.4 −32.1 9.6 −30.4 102 23.1 7.9 11.1 −36.9−43.1 −36.7 −27.6 −44.6 −45.5 −30.2 14.0 −37.8 108 10.8 −1.6 1.9 −32.3−41.5 −43.3 −31.0 −48.2 −49.1 −35.8 3.7 −40.2 120 13.8 4.8 3.7 −24.6−32.3 −28.3 −20.7 −30.4 −43.6 −30.2 7.4 −30 144 23.1 0.0 13.0 −32.3−38.5 −38.3 −24.1 −35.7 −40.0 −37.7 12.0 −35.2 168 4.6 −6.3 1.9 −36.9−44.6 −38.3 −24.1 −37.5 −40.0 −45.3 0.1 −38.1 192 12.3 −4.8 1.9 −32.3−41.5 −40.0 −17.2 −35.7 −43.6 −39.6 3.1 −35.7 216 15.4 −3.2 22.2 −32.3−32.3 −35.0 −24.1 −41.1 −25.5 −43.4 11.5 −33.4 222 16.9 6.3 25.9 −38.5−40.0 −38.3 −32.8 −44.6 −41.8 −41.5 16.4 −39.6 228 9.2 −1.6 16.7 −36.9−40.0 −43.3 −36.2 −44.6 −41.8 −47.2 8.1 −41.4 240 6.2 1.6 18.5 −27.7−30.8 −33.3 −25.9 −26.8 −34.5 −39.6 8.8 −31.2 246 −3.1 −9.5 9.3 −32.3−38.5 −36.7 −29.3 −30.4 −40.0 −43.4 −1.1 −35.8 252 −10.8 −15.9 0.0 −35.4−43.1 −45.0 −31.0 −32.1 −41.8 −45.3 −8.9 −39.1 264 −12.3 −15.9 5.6 −32.3−38.5 −33.3 −27.6 −26.8 −27.3 −37.7 −7.5 −31.9 270 −13.8 −15.9 1.9 −23.1−32.3 −25.0 −13.8 −16.1 −27.3 −22.6 −9.3 −22.9 288 −12.3 −14.3 1.9 −24.6−33.8 −31.7 −17.2 −14.3 −23.6 −28.3 −8.2 −24.8 312 −13.8 −3.2 7.4 −13.8−27.7 −18.3 −5.2 −7.1 −10.9 −13.2 −3.2 −13.7 Timepoint in bold = dosingtimepoints Timepoints 222 and greater = post dosing

Example 6C: Multi-Dose Clinical Trial Results for Group 9

2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acidwas evaluated according to the clinical trial described above in Example5.

Results for eleven subjects in group 9, receiving 10 mg active orplacebo, once daily for 10 days, are shown below. Subjects 1 and 2received placebo; subjects 3-11 received active.

Absolute sUA concentrations (mg/dL) by nominal timepoint (i.e. days0-9—once daily dosing, plus days 10-13, post dosing) are shown in thetable below, and presented in graphical form in FIG. 9A.

Absolute sUA concentration (mg/dL) Subject Number Mean Mean Time 1 2 3 45 6 7 8 9 10 11 Placebo (3-11) 0 7.8 5.8 8.0 7.3 6.8 6.6 6.4 6.2 5.6 5.45.2 6.8 6.4 6 8.0 6.0 6.2 5.2 4.4 4.5 4.1 4.2 4.1 4.0 3.5 7.0 4.5 12 7.55.8 6.5 4.7 4.1 3.2 3.5 4.2 3.6 3.8 3.0 6.7 4.1 24 7.8 6.1 6.8 5.2 4.03.3 4.2 4.2 4.8 3.6 3.2 7.0 4.4 48 8.3 6.8 5.5 5.1 3.3 3.6 4.4 4.0 4.73.4 3.3 7.6 4.1 72 7.3 6.0 4.4 4.0 2.7 3.0 3.6 3.0 3.5 2.6 2.2 6.7 3.296 6.7 5.6 3.9 3.7 2.3 2.9 3.1 2.8 3.2 2.5 2.2 6.2 3.0 102 7.0 6.2 3.93.1 2.4 3.0 3.4 2.7 2.8 2.7 1.8 6.6 2.9 108 6.6 5.9 3.9 3.0 2.1 2.3 3.12.8 2.8 2.7 1.9 6.3 2.7 120 7.3 6.2 4.6 3.8 2.7 2.9 3.8 3.6 3.6 2.9 2.56.8 3.4 144 7.6 6.0 4.8 3.5 2.8 3.1 3.8 4.7 3.6 3.0 2.6 6.8 3.5 168 7.25.9 4.9 3.2 2.4 2.9 3.3 4.1 3.3 2.5 2.4 6.6 3.2 192 6.8 5.5 4.2 3.0 2.02.3 3.2 3.1 3.1 2.3 2.2 6.2 2.8 216 7.3 6.0 4.5 3.2 2.4 2.9 NA 3.2 3.52.6 2.5 6.7 3.1 222 7.6 6.1 3.9 2.6 2.1 2.6 NA 2.7 3.4 2.6 2.3 6.9 2.8228 7.4 6.1 3.7 2.4 2.1 2.3 2.9 2.5 3.1 2.7 2.3 6.8 2.7 240 7.8 6.2 4.93.6 2.7 2.5 4.1 3.1 3.6 2.4 2.7 7.0 3.3 246 7.6 6.1 5.4 3.6 3.2 3.2 4.33.6 4.0 2.5 3.1 6.9 3.7 252 7.3 6.0 5.3 3.3 3.1 3.1 4.4 3.9 3.7 2.7 2.96.7 3.6 264 7.1 6.0 5.7 3.6 3.4 3.7 4.9 4.2 3.8 2.7 3.2 6.6 3.9 270 6.75.8 5.7 3.8 3.5 4.2 5.1 4.6 4.0 2.7 3.2 6.3 4.1 288 6.4 5.4 5.7 4.0 3.74.4 4.8 4.8 3.9 2.8 3.3 5.9 4.2 312 6.8 5.7 6.5 4.8 4.3 5.0 5.5 5.2 4.33.3 3.8 6.3 4.7 Timepoint in bold = dosing timepoints Timepoints 222 andgreater = post dosing% sUA change (from baseline) by nominal timepoint (i.e. days 0-9—oncedaily dosing, plus days 10-13, post dosing) are shown in the tablebelow, and presented in graphical form in FIG. 9B.

% sUA change (from baseline) Subject Number Mean Mean Time 1 2 3 4 5 6 78 9 10 11 Placebo (3-11) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 6 2.6 3.4 −22.5−28.8 −31.8 −35.9 −35.3 −32.3 −26.8 −25.9 −32.7 3.0 −30.2 12 −3.8 0.0−18.8 −35.6 −39.7 −51.5 −45.3 −35.7 −32.3 −29.6 −42.3 −1.9 −36.8 24 0.05.2 −15.0 −28.8 −41.2 −50.0 −34.4 −32.3 −14.3 −33.3 −38.5 2.6 −32.0 486.4 17.2 −31.3 −30.1 −51.5 −45.5 −31.3 −35.5 −16.1 −37.0 −36.5 11.8−35.0 72 −6.4 3.4 −45.0 −45.2 −60.3 −54.5 −43.8 −51.6 −37.5 −51.9 −57.7−1.5 −49.7 96 −14.1 −3.4 −51.3 −49.3 −66.2 −56.1 −51.6 −54.8 −42.9 −53.7−57.7 −8.8 −53.7 102 −10.3 6.9 −51.3 −57.5 −64.7 −54.5 −46.9 −56.5 −50.0−50.0 −65.4 −1.7 −55.2 108 −15.4 1.7 −51.3 −58.9 −69.1 −65.2 −51.6 −54.8−50.0 −50.0 −63.5 −6.9 −57.2 120 −6.4 6.9 −42.5 −47.9 −60.3 −56.1 −40.6−41.9 −35.7 −46.3 −51.9 0.3 −47.0 144 −2.6 3.4 −40.0 −52.1 −58.8 −53.0−40.6 −24.2 −35.7 −44.4 −50.0 0.4 −44.3 168 −7.7 1.7 −38.7 −56.2 −64.7−56.1 −48.4 −33.9 −41.1 −53.7 −53.8 −3.0 −49.6 192 −12.8 −5.2 −47.5−58.9 −70.6 −65.2 −50.0 −50.0 −44.6 −57.4 −57.7 −9.0 −55.8 216 −6.4 3.4−43.8 −56.2 −64.7 −56.1 NA −48.4 −37.5 −51.9 −51.9 −1.5 −51.3 222 −2.65.2 −51.3 −64.4 −69.1 −60.6 NA −56.5 −39.3 −51.9 −55.8 1.3 −56.1 228−5.1 5.2 −53.8 −67.1 −69.1 −65.2 −54.7 −59.7 −44.6 −50.0 −55.8 0.1 −57.8240 0.0 6.9 −38.7 −50.7 −60.3 −62.1 −35.9 −50.0 −35.7 −55.6 −48.1 3.5−48.6 246 −2.6 5.2 −32.5 −50.7 −52.9 −51.5 −32.8 −41.9 −28.6 −53.7 −40.41.3 −42.8 252 −6.4 3.4 −33.8 −54.8 −54.4 −53.0 −31.3 −37.1 −33.9 −50.0−44.2 −1.5 −43.6 264 −9.0 3.4 −28.8 −50.7 −50.0 −43.9 −23.4 −32.3 −32.1−50.0 −38.5 −2.8 −38.9 270 −14.1 0.0 −28.8 −47.9 −48.5 −36.4 −20.3 −25.8−28.6 −50.0 −38.5 −7.1 −36.1 288 −17.9 −6.9 −28.8 −45.2 −45.6 −33.3−25.0 −22.6 −30.4 −48.1 −36.5 −12.4 −35.1 312 −12.8 −1.7 −18.8 −34.2−36.8 −24.2 −14.1 −16.1 −23.2 −38.9 −26.9 −7.3 −25.9 Timepoint in bold =dosing timepoints Timepoints 222 and greater = post dosingAbsolute sUA and % sUA change by nominal timepoint (i.e. days 0-9—oncedaily dosing, plus days 10-13, post dosing) for groups 7, 8 and 9 (1 mg,5 mg and 10 mg, all fasted; placebo groups pooled) are presented ingraphical form in FIGS. 10A and 10B respectively.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested toindividuals skilled in the art are to be included within the spirit andpurview of this application and scope of the appended claims.

What is claimed is:
 1. A method for reducing serum uric acid levels in ahuman, comprising administering to the human between about 2 mg and lessthan 10 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein about 4 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt, is administered to the human. 3.The method of claim 1, wherein about 2 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt, is administered to the human. 4.The method of claim 1, wherein about 5 mg per day of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt, is administered to the human. 5.The method of claim 1, wherein between about 2 mg and about 5 mg per dayof 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoicacid, or a pharmaceutically acceptable salt, is administered to thehuman.
 6. The method of claim 1, wherein 24 hours after administrationof 2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoicacid, the serum uric acid levels are reduced by at least 15% frombaseline.
 7. The method of claim 1, wherein 24 hours afteradministration of2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,the serum uric acid levels are reduced by at least 20% from baseline. 8.A method for treating a condition in a human comprising administering tothe human between about 2 mg and less than 10 mg per day of2-((3-4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid,or a pharmaceutically acceptable salt thereof; wherein the condition isselected from the group consisting of gout, a recurrent gout attack,gouty arthritis, hyperuricemia, hypertension, coronary heart disease,Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, kidneystones, kidney failure, joint inflammation, arthritis, urolithiasis,plumbism, hyperparathyroidism, psoriasis, sarcoidosis,hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency or acombination thereof; and wherein serum uric acid levels in the human arereduced.
 9. The method of claim 8, wherein the condition is gout. 10.The method of claim 1, wherein a second agent effective for thetreatment of the gout is administered to the human.
 11. The method ofclaim 10, wherein the second agent is a URAT 1 inhibitor, a xanthineoxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductaseinhibitor, or combinations thereof.
 12. The method of claim 11, whereinthe URAT 1 inhibitor is2-((5-bromo-4-(4-cyclopropyl-1-naphthalenyl)-4H-1,2,4-triazol-3-yl)thio)aceticacid, or a pharmaceutically acceptable salt thereof.
 13. The method ofclaim 11, wherein the xanthine oxidase inhibitor is allopurinol orfebuxostat.